Mr. Chairman and Members of the Committee, my name is Joseph A. Levitt, Director,
Center for Food Safety and Applied Nutrition (CFSAN), Food and Drug Administration (FDA or
Agency). I am joined by Janice F. Oliver, Deputy Director, CFSAN and Elizabeth A. Yetley,
Ph.D., Director, Office of Special Nutritionals, CFSAN. I am pleased to be here today to
discuss FDAs adverse event reporting systems generally, and specifically,
CFSANs Adverse Event Monitoring System called SN/AEMS, which is for special
nutritional products, including dietary supplements. In meeting the Agencys mission,
one of our responsibilities is to monitor marketed medical products, foods, cosmetics, and
dietary supplements for unexpected adverse events. FDA surveillance programs alert the
Agency to potential threats to the public health and help Agency experts identify the need
for preventive actions.
As Jane E. Henney, M.D., Commissioner of Food and Drugs, stated on March 25, 1999
during a hearing before this Committee, the Dietary Supplement Health and Education Act of
1994 (DSHEA) amended the Federal Food, Drug, and Cosmetic Act to define the term
"dietary supplement" and to establish a regulatory framework for dietary
supplements. DSHEA provides broad access to dietary supplements for consumers and
recognizes that there is a need for a rational regulatory framework that provides FDA
authority to remove from the market products that pose a "significant or
unreasonable" risk to consumers and that are otherwise adulterated, and to require
that labeling for dietary supplements be accurate. The SN/AEMS system is a critical part
of FDAs ability to meet the consumer protection provision of the law. While the
current system has served the Agency well thus far, we believe there are enhancements to
the SN/AEMS system that certainly should occur. We welcome this opportunity to continue
that dialogue with you.
Let me begin by providing a brief overview of the adverse event reporting system for
drugs, highlighting the purpose and differences of that system compared to the system for
special nutritionals, which include dietary supplements. Then, I will specifically discuss
the system at CFSAN for monitoring adverse event reports for dietary supplements. For your
information, a brief summary of the adverse event reporting systems for all other
FDA-regulated products is included in an Appendix to this testimony.
As you know, FDA's responsibilities include postmarketing evaluation, which includes
risk surveillance and assessment that rely primarily on two methods of adverse event
reporting to the Agency: 1) direct, voluntary reporting by concerned parties, including
health professionals and consumers; and, 2) mandated reporting by drug (including
biologics) and device manufacturers, distributors, and medical device user facilities.
Under the current system, FDA shares this responsibility with manufacturers, healthcare
providers, user facilities, patients and consumers. Each participant has a role in
monitoring and evaluating adverse events associated with medical products, foods, and
cosmetics. The roles assigned to manufacturers and FDA are defined primarily by statute,
while the roles of others are not.
The specific objectives of FDAs postmarketing risk assessment programs are to:
- detect adverse events not previously observed,
- for drugs, biologics, or medical devices, improve understanding of the potential
severity of previously anticipated risks, listed on the products labeling,
- detect adverse events resulting from multiple possible interactions, such as drug
interactions or drug-food interactions.
These reporting systems serve as an early warning signal for identifying potential
Changes in the Postmarket Surveillance Environment
Changes are occurring in several areas that will affect the Agencys current
postmarketing surveillance systems. First, the Prescription Drug User Fee Act and the FDA
Modernization Act of 1997 have resulted in some changes in postmarketing reporting
requirements. For example, with regard to medical devices, the Modernization Act directs
FDA to move away from universal, mandatory adverse event reporting by user facilities to a
system based on reporting by a representative sample of facilities.
In addition, shifts in the health care environment and in international marketplaces
are affecting the potential for adverse events caused by medical interventions. For
example, with patients now being treated by multiple healthcare providers, a single
provider may not have full knowledge of the patients medical history and use of
various medicines and other products. A prescriber's lack of information can lead to
increased risk of drug interactions, as one physician may not be aware of what another has
prescribed or recommended. The dietary supplement industry has grown dramatically, as has
consumption of dietary supplements. Surveys show that more than half of the U.S. adult
population uses dietary supplement products. The increasingly global marketplace also
could result in a greater potential for rapid, large-scale consumer exposure to new
products, which carries a proportional potential for more unexpected adverse events.
Finally, the rapid development of new medical interventions for a variety of previously
untreatable (or less satisfactorily treatable) conditions results in more individuals
using these new interventions. These shifts in the healthcare environment are challenging
the existing system and should be considered as we examine FDA's adverse event reporting
or monitoring systems.
Adverse Event Reporting Systems
While the U.S. has one of the most rigorous premarket approval processes in the world,
it is not possible to detect all potential problems during premarketing clinical trials of
drugs and medical devices, or premarketing evaluation of the safety of food additives. In
addition, not all products that FDA regulates require premarket approval - such as dietary
supplements, conventional foods, and cosmetics. The need for postmarketing surveillance is
the direct result of these limitations.
FDA receives spontaneous reports of suspected adverse events from manufacturers,
user facilities, healthcare professionals, and consumers. Through a program called "MEDWATCH, the FDA Medical Products Reporting
Program," healthcare professionals and consumers are encouraged to report serious
adverse events and product problems to FDA, the manufacturer, or both. MEDWATCH has established four methods for the public to report to FDA: phone
(via a toll-free number), fax (via a toll-free number), direct mail (using a postage paid
form), and Internet (via the interactive form on the MEDWATCH website).
MEDWATCH was announced June 3, 1993. While
FDA's longstanding postmarketing surveillance programs predate MEDWATCH, this educational initiative was designed to enhance the
identification and reporting of adverse events related to the use of FDA-regulated
products. Through the MEDMEDWATCH program, health
professionals can report serious adverse events and product problems that occur with such
medical products as drugs, biologics, medical and radiation-emitting devices, and special
nutritional products (i.e., medical foods, dietary supplements and infant formulas). When
a health care professional suspects that a product may be related to a serious event, FDA
encourages the health professional to submit a MEDWATCH
report. Health professionals, however, are welcome to report any adverse event that they
judge to be clinically significant.
Adverse Event Reports come into FDA in many ways - either through MEDWATCH, where they are transferred to the appropriate Center; directly to
the Center; or through an FDA District or Field Office. Regardless of the path into the
Agency, reports are directed to the appropriate Center to be recorded and reviewed.
Strengths and Limitations of Spontaneous Reports Data
For medical devices and drugs (including biologics) adverse event reporting or
monitoring systems serve as critical tools to identify potential health hazards that were
not anticipated or identified in pre-market safety evaluations. In the absence of
premarket review data, the SN/AEMS serves as a critical source for gathering data about
the safety of dietary supplements. These systems serve to augment, not replace, other
systems and tools for determining the safety of products. Like all passive surveillance
systems, however, there are strengths and certain limitations.
The strengths include:
- Generation of Hypotheses and Signals: The great utility of spontaneous report-based
surveillance programs is to generate signals of potential public health problems that
warrant further investigation. For this reason, adverse event reports must be evaluated in
the context of other information, which may include controlled clinical trials, case
reports in the scientific literature, the known physiological and pharmacological effects
of the substance suspected of being associated with adverse events, market and consumer
surveys, and product analysis.
- Clinician Contribution: Health professionals often identify and document adverse events
in the clinical settings in which they work. They can provide in-depth information in the
adverse event report, thereby providing key input to any postmarketing surveillance
system. Thus, while possessing inherent limitations, postmarketing surveillance based on
spontaneous report data from clinicians is a particularly powerful tool for detecting
adverse event signals of direct clinical impact.
The limitations include:
- Underreporting: Adverse events associated with product use are known to be significantly
underreported, since many consumers and health professionals may not recognize a link
between the use of a particular product and a subsequent injury or illness, or they do not
report the adverse event to appropriate health care agencies. Indeed, because reporting is
voluntary (except in the case of certain adverse events that childhood vaccine health care
providers, device user facilities, and drug and device manufacturers must report), adverse
events which are not reported almost certainly occur.
- Report Quality: Under research protocols, information is collected in a systematic and
standardized manner to test a particular hypothesis, and such protocols include numerous
quality control procedures to assure reliability and validity of data collected. By
contrast, a passive surveillance system is dependent on information contained in voluntary
reports from consumers, family, friends, or from health professionals based on patient
information and evaluations. FDA attempts to obtain follow-up data to add to the
completeness, clarity, and relevance of a report that associates a clinically serious
event with the use of regulated products. Success in obtaining such information, however,
is variable. Thus, information received in a passive reporting system is not standardized
and often is incomplete. Nonetheless, the reports provide valuable public health
information on potential safety problems. Where there is a basis for concern, prudent
public health policy leads FDA to take action to protect against unsafe uses of marketed
- Adverse Event Recognition: An attribution between the product and the observed event may
not be assumed with all spontaneously reported events. This consideration emphasizes the
crucial need for careful, thoughtful review of adverse event reports upon their receipt by
FDA or the manufacturer and the review of other available scientific information.
- Biases: Unlike clinical trial data, which are obtained under strictly controlled
conditions, spontaneously reported information is uncontrolled, and therefore subject to
the possible influence of a number of biases that can affect reporting. These biases
include the length of time a product has been on the market, country, reporting
environment, and quality of the data.
- Estimation of Population Exposure: As a general matter, accumulated case reports cannot
be used to calculate incidence rates. Numerator and denominator limitations described
above make incidence rates computed from spontaneously reported data problematic.
Compounding these numerator limitations is the lack of denominator data, such as user
population and product exposure patterns, that would provide the exact number of
consumers exposed to the medical product, and thus at risk for the adverse event of
interest. Even if the exposed population is not precisely known, however, estimation of
the exposure can be attempted through the use of product utilization data, when it is
available for the product. This approach, whose basic methodologies are applicable to
medical products in general, can be of great utility. Such utilization data are not
available, however, for dietary supplement products, and so making confident estimates of
overall exposure in the population is generally not feasible.
FDA Evaluation of Reports of Adverse Events
The very nature of spontaneously reported data places great importance on the
evaluation of submitted reports of adverse events. This process is perhaps most accurately
characterized as a method, applied on a case-by-case basis, that is based on experience,
knowledge of the product being monitored, and awareness of the strengths and limitations
of the data.
Spontaneous reporting systems Center for Drug Evaluation and Research
In the case of pharmaceuticals, FDA pays particular attention to all reported serious
adverse events that are not in product labeling. Other reports are entered into the
database for use in aggregate analysis. In focused evaluation of adverse events, the
postmarketing surveillance database is searched for other reports, and further steps are
taken, such as literature searches and use of medical product utilization databases.
Adverse Event Reporting System (AERS)
The Center for Drug Evaluation and Research (CDER) uses a passive, spontaneous
reporting system to provide monitoring capability to detect rare and unexpected adverse
reactions to marketed drugs. Data are generated primarily as "spontaneous"
reports observed and reported by practicing health care practitioners i.e., reports
that originate from observations made in the usual practice of medicine.
FDA began computerizing adverse drug reaction reports (ADRs) in the mid-1960s and
legacy data is available dating back to 1969. This computerized system, called the
Spontaneous Reporting System (SRS), was replaced by the newer Adverse Event Reporting
System (AERS) in November 1997. It is the cornerstone system providing technology for
safety monitoring of "spontaneous" data for CDER and the Center for Biologic
Evaluation and Research (CBER) therapeutic agents. Currently, adverse drug reactions are
reported to FDA in a variety of ways and provide a database of some two million reports
that can be analyzed individually or in the aggregate. In FY1998, more than 230,000
reports of suspected adverse events were received by AERS.
Reports of adverse events on marketed human drugs and non-vaccine biologics include
prescription drugs (whether or not they are the subject of an approved New Drug
Application (NDA)), generic drugs, over-the-counter (OTC) drugs that are the subject of an
approved NDA and non-vaccine biologics. These reports reach FDA through either the
drug/biologic manufacturers or direct contact (MEDWATCH).
When a health practitioner notifies a manufacturer about a possible reaction, the
manufacturer is required by law and regulations to report these observations to FDA.
There are two major sources of OTC drug adverse event reports in FDA:
- Manufacturers of OTC drugs with NDAs are required by the postmarketing regulation
(21 CFR 314.80) to report any serious and unexpected adverse events in 15 days and other
type reports periodically as specified by the regulations the same as for
prescription drugs. Given that most of these agents have been on the market for many years
and safety of the drugs have been monitored extensively, very rarely are new and rare
adverse events identified. More frequently reports are consumers complaints of lack
of expected effect, which is usually a subjective measurement of efficacy (or lack
- Voluntary reporting of OTC monographed drugs by consumers or manufacturers is a second
source of data. These are greater than 300,000 individual OTC products with more than 700
active ingredients under OTC monographs in place or under development. As expected where
these drugs are used appropriately, most adverse events are not serious but in an effort
to standardize safety reporting, FDA is considering a proposed regulation mandating
reporting of all serious reports, expeditiously, to monitor the rare adverse events and
potential product or manufacturing problems.
A minimum data set for a report is currently defined as a report having an identified
drug/therapeutic, a definable reaction, a reporter and a patient or subject. For an
adverse reaction report to be interpretable, it must contain descriptions of the reaction,
the exposure to the drug/therapeutic, the temporal relationship between exposure and
reaction, and the underlying disease.
Substantial effort is placed on the review of the case reports for purposes of
identifying those with serious outcomes involving adverse event reports not currently in a
drug/therapeutic products labeling. The goal of evaluation of
"spontaneous" data is to provide a signal that can be evaluated, quantified and
validated as a drug/therapeutic outcome and to ensure appropriate dissemination of risk
management information and initiation of regulatory action. Typically, this information
may result from as few as several well-documented cases to a very large number of reports
that are then evaluated and subjected to signal development. This process involves
application of epidemiological methods and includes clinical evaluation of cases for the
conditions relating to drug exposure and for the identification of potential risk factors,
and confounders of the adverse event reports occurrence. It also includes
demographic description and quantification of the exposed population. In the best of
circumstances, estimates of reporting rates are possible, using the reported number of
adverse event report cases as the numerator and an estimate of prescription drug use as
the denominator. At this point in the process, additional data, derived from literature
sources, observational or clinical studies, linked databases or other sources of drug
usage data are considered to strengthen or clarify the reported observations for
When a signal of a potential adverse reaction is detected, safety evaluators consult
with product reviewers, medical officers, and epidemiologists to review available data and
consider further options. Focused studies may be undertaken using various epidemiological
and analytical databases and other resources. Based on the results of these studies and
evaluations, FDA may decide to disseminate risk information, such as Dear Healthcare
Professional letters, and may initiate regulatory action.
Characteristics That Support Drug Spontaneous Reporting
The following characteristics are important in ensuring that the current system is
effective in identifying serious, unlabeled events of interest via the spontaneous system
for drugs. In general, these are not features of Special Nutritional products reporting:
- Manufacturer Reporting vs. Direct Reporting
Spontaneous reporting of Adverse Event for drugs is heavily driven by Manufacturer
Reporting (some 90% of all reports received). Manufacturer reporting (except for OTC
monograph drugs) is required by regulation, is well accepted, and leverages the
firms resources in identifying, assessing, and following up on reports of drug
Current good manufacturing practice requirements for all firms manufacturing, labeling,
and distributing drugs in the U.S. provides a basis for assuring that the agent identified
in the report is the drug in question with the contents meeting the appropriate standards
of potency, strength, and purity.
The Drug Label provides information for the indication and safe and effective use of
the product as well as information on the known adverse effects and contraindications.
Premarket clearance for drugs (except for OTC monograph drugs) provides data for an
initial assessment at the point of approval of the benefit risk assessment and a
good starting point for evaluating the agent when it goes beyond the target population
The benefit-risk assessment is the continuing process of evaluating the new risks seen
postmarketing against the known benefits of the drug. Again, premarket clearance provides
a basis for comparison as the safety picture evolves.
- Additional Aspects of Drug Pharmacovigilance
By regulation, serious unlabeled foreign reports are reported to CDER, providing a
broader view to the overall benefit risk picture, sometimes world-wide. In
addition, the benefits of 30 years of reporting have resulted in a system that is widely
accepted by corporate culture. The Agency also provides regulation, guidance, and
compliance oversight to ensure good reporting practices. Finally, evolving regulations
reflecting the International Conference on Harmonization (ICH) initiatives and focusing on
standardization of requirements have been widely discussed and accepted by industry.
- Learned Intermediary
For prescription drugs, the intervention of a "learned intermediary" (variety
of health practitioners) provides a mechanism to supply ongoing individual risk-benefit
assessment in the practice of medicine, pharmacy, etc. and to provide a conduit for
reporting adverse events.
Let me now address FDAs spontaneous reporting system for dietary supplements.
Spontaneous reporting system for dietary supplements
Special Nutritionals Adverse Event Monitoring System (SN/AEMS)
The SN/AEMS was established in early 1993, following the establishment of the Office of
Special Nutritionals. The SN/AEMS system, while formally part of CFSANs Adverse
Reaction Monitoring System, is still in its infancy when compared to the more formal and
well-developed adverse event reporting systems that exist for other products regulated by
FDA. It provides, however, 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 products already in the marketplace that need to be investigated and critically
SN/AEMS is limited to those adverse events reported with the use of special nutritional
products, which include dietary supplements, infant formulas, and medical foods. The
adverse events received on special nutritional products include a variety of both acute
and chronic adverse effects. Typically, special nutritional products are used for
prolonged periods and often by special or vulnerable populations. Furthermore, dietary
supplements often contain multiple substances that may have physiological or even
pharmacological effects. The adverse events seen with these products, therefore, tend to
require extensive follow-up and evaluation.
Because of these factors, when a serious adverse event is reported in association with
a dietary supplement product, considerable resources are expended by FDA to obtain even
basic information on the product (e.g., the product name, manufacturer, ingredients, and
directions for use). Information is also needed on how the consumer used the product and
the nature, severity, patterns, and outcome of the adverse event. Given that reported
safety information is limited for most dietary supplement products, SN/AEMS is a critical
tool for identifying new or emerging public health problems that may be associated with
the use of particular products. Further, the signals generated by SN/AEMS help focus
Agency resources on products needing further investigation. Compared to the CDER adverse
event reporting system, the SN/AEMS lacks many of the tools at CDERs disposal
premarket testing database, mandatory reporting by manufacturers, registration of firms
and listing of products, good manufacturing practice requirements, and a mature internal
database system with which to manage the wealth of information they receive.
These are some of the challenges CFSAN faces with the current system and we are working
to address the many areas that will make the system stronger. Specifically, based on the
Agencys FY 2000 budget request, CFSAN is developing plans to recruit and train
additional appropriate medical staff, and enhance the SN/AEMS system, including
integration into an FDA-wide system. A major emphasis will be placed on upgrading and
improving the computer infrastructure to facilitate signal and report generation. In
addition, as you know, FDA now provides summary information on its special nutritionals
AER database on its homepage (www.fda.cfsan.gov).
Interested persons may either browse the web report or search for specific ingredients,
reports, or types of adverse events. Since its inception, this web site has been very
popular. On average it is accessed approximately 3,000 4,000 times per month.
We heard the concerns the Committee raised at the March 25 hearing regarding correcting
errors to records on the web, and concerns both the Committee and industry have raised
about access to those records under the Freedom of Information Act (FOIA). Providing
industry access to accurate information in a timely manner, within the boundaries of the
FOIA, and having sufficient resources to apply to maintaining accurate web site records on
a real time basis are issues CFSAN is grappling with. We would welcome further discussion
with the Committee on these issues.
Like the adverse event reporting system for CDER, the SN/AEM system also receives
information from a variety of sources, as identified in Chart A. For dietary
supplements, all such reporting is voluntary. As you can see in Chart B, when CFSAN
receives a suspected adverse event report on a dietary supplement, it conducts an initial
review to determine the seriousness or clinical significance of the report. If the report
is considered serious or clinically significant, immediate follow-up information is
requested if needed.
The requested follow-up information may include copies of the product(s) label and
labeling, information on how the consumer used the product(s), and available medical or
other clinical records concerning the reported adverse event. As noted above, the
Agencys ability to follow-up has potential limitations based on a variety of
factors, e.g., the product sample has often been discarded. After the initial review,
CFSAN conducts a medical/clinical review and evaluation to determine whether the report
signals a potential public health problem, and if so, what action the Agency should take.
In addition to efforts within FDA to ensure the safe use of dietary supplements,
education of the public in an appropriate and timely manner about potential adverse
effects associated with these products is critical. In an era of limited resources, the
coordinated efforts of Federal agencies, academia, public health groups, industry, and
consumers will be required. As you may recall, when Dr. Henney testified on March 25, she
mentioned the Agencys commitment to developing, this calendar year, an overall
strategy for achieving effective regulation of dietary supplements under DSHEA. Dr. Henney
also stated that in doing so, FDA will provide ample opportunity for public input. As part
of this ongoing consultation with FDAs stakeholders, the Agency will hold public
meetings on June 8, 1999, in Washington, D.C., and on July 20, 1999, in Oakland,
California, to solicit comments that will assist CFSAN in the development of that
strategy, including input on the SN/AEM system. Finally, as noted last year in FDAs
response to the Report of the Commission on Dietary Supplement Labels, FDA has asked our
Foods Advisory Committee (FAC) to play an active role in two important issues: First, to
consider how best to gather data on how consumers use information on dietary supplement
labels to make decisions as to whether or not a dietary supplement is appropriate for
them. FDA asked the FAC to consider the development of guidelines or criteria that could
be used by the dietary supplement industry and others to conduct consumer research studies
or to evaluate the results of consumer research studies; and, Second, to consider the
issue of postmarket surveillance and particularly how best to collect and share
surveillance information. The FAC considered these issues at their February 1998 meeting
and referred them to FAC working groups to develop recommendations for consideration by
the full Committee. The Agency also is considering whether to establish a separate
Advisory Committee or Expert Panel devoted to dietary supplement issues, an idea that was
also raised at the March 25 hearing.
How AER's Benefit Public Health
While there certainly are limitations to passive spontaneous reporting systems, as I
have outlined above, I would like to discuss a few examples of how these systems have
provided a great benefit to public health.
Adverse Event Reporting System (AERS)
Tasmar (tolcapone) was approved on January 29, 1998, as adjunct therapy (with levodopa
and carbidopa) for the treatment of the signs and symptoms of idiopathic Parkinsons
disease. The labeling included (in the Precautions Section) a statement on reversible
hepatic enzyme abnormalities and recommended monthly monitoring during the first three
months of treatment and every six weeks for the following three months. Recommendations
also included discontinuing the drug when enzyme elevations equaled or exceeded five times
the upper limit of normal, or at the appearance of jaundice. Postmarketing surveillance
identified 17 cases of liver-related adverse events following approval including: five
hepatitis, three jaundice, and nine other liver function abnormalities. Five pivotal cases
were identified with hepatitis documented with increased hepatic transaminase levels and
biopsy/radiographic examination suggesting likely drug induced hepatitis related to Tasmar
therapy. Two of the five cases reported fatalities from fulminate hepatitis or liver
failure from less than three months of therapy- one from Switzerland and one from the U.S.
All five pivotal cases experienced hepatitis within six weeks of therapy that was
initially undetected, potentially due to lack of adequate monitoring of liver functions as
recommended in the labeling.
In November 1998, FDA asked the sponsor of Tasmar to revise the labeling to include the
new warning on hepatotoxicity and a "Dear Doctor" Letter was sent to alert the
prescribing physicians and patients with a new requirement of liver function monitoring
every two weeks during Tasmar treatment. Since November 1998, FDA has not received any
more serious case reports of liver related injuries associated with Tasmar.
Special Nutritionals/Adverse Event Reporting System
In our March 25 testimony, we referenced this case as an example of how the Agency uses
a variety of regulatory tools from enforcement actions to rulemaking when it has found
dietary supplements that cause safety concerns. This case also is a good example of how
AERS serve as our early warning signal and how just one AER can be a powerful indicator of
a safety concern.
In 1997, FDA received an AER regarding a young woman with life-threatening
abnormal heart function who required hospitalization for six days. FDA immediately
conducted an investigation. The Agency detected the botanical Digitalis lanata in
samples of raw material labeled "plantain" that was an ingredient in one of the
dietary supplement products used by this young woman. Digitalis is a powerful heart
stimulant whose effects may include nausea, vomiting, dizziness, headache, confusion,
hypotention (low blood pressure), vision disturbances, and abnormal heart rate and rhythm.
FDA then traced all uses of the contaminated ingredient and asked manufacturers and
retailers to recall these products from the market. FDA issued several press releases
warning consumers not to purchase or ingest certain dietary supplement products labeled as
containing plantain because these products may contain Digitalis lanata, a plant
that can cause life-threatening heart reactions, including cardiac arrest, if ingested.
While fast and effective actions by FDA prevented further serious adverse effects, which
would have likely occurred if these contaminated products remained in the marketplace, it
was a single AER that led the Agency to take action.
Gamma butyrolactone (GBL) is a metabolic precursor to gamma-hydroxybutyrate (GHB), an
unapproved new drug and one of the "date rape" drugs. GBL is promoted as a
dietary supplement with claims to stimulate growth hormone release, fight stress, increase
athletic performance, combat aging, promote sleep, as well as other uses. It is a
manufacturing intermediate and industrial solvent. Products containing GBL have been
marketed under various brand names, including Renewtrient, Revivarant or Revivarant G,
Blue Nitro or Blue Nitro Vitality, GH Revitalizer, Gamma G, Invigorate, and Remforce. GBL
has been associated with serious, life-threatening adverse events and the Agency has
initiated action to remove it from the marketplace.
FDA had received 55 reports of adverse events by January 13, 1999 (95 AER's as of
February 26, 1999), including one death. In 19 of those cases, the consumers became
unconscious or comatose and several required intubation for assisted breathing. Other
reported effects included seizures, vomiting, slow breathing, and slow heart rate. There
were reports of at least five children under 18 years of age who have been injured or who
have suffered these kinds of effects.
FDA's analysis of available scientific information, including the opinion of
independent outside scientific/medical experts, concluded that GBL's presence in the
marketplace represented a serious public health hazard due to its steep dose response
curve, ability to induce respiratory arrest and coma, and its serious abuse potential. The
Agency concluded that label information, such as warning/caution statements and directions
for use, could not provide for its safe use. FDA issued a public warning on January 21,
1999, alerting consumers of the potential hazards from consumption of GBL-containing
Firms known to produce or distribute GBL were contacted beginning on January 19, 1999.
Warning letters were delivered, beginning on January 27, 1999, to firms not voluntarily
recalling their products. The warning letters state that FDA considers GBL to be an
unapproved new drug, that these products do not meet the statutory requirement to be
marketed as a dietary supplement, and that, even if they could be considered dietary
supplements, they do not meet the safety requirements of the law. As of May 20, 1999, FDA
has initiated two court-ordered seizures of GBL-containing products.
As you know, on June 4, 1997, FDA published in the Federal Register a proposed
rule on Dietary Supplements Containing Ephedrine Alkaloids (62 FR 30678). There are a
variety of opinions about the proposed rule and the direction the Agency should take. One
cannot dispute, however, the shear volume of the reports of illness and injuries that FDA
received reported to be associated with the use of dietary supplements suspected to
contain ephedrine alkaloids.
Between 1993 and mid-1996, FDA received about 1,600 AER's reported to be associated
with the use of dietary supplement products in general. Of these, over half of the AER's
were reported to be associated with the use of dietary supplements that contained, or were
suspected to contain, ephedrine alkaloids. These adverse events tended to involve
cardiovascular system effects and nervous system effects. FDA evaluated these reports and
found that the single most common element was that the products contained, or were thought
to contain, a source of ephedrine alkaloids (62 FR 30679).
FDA used the information available in the approximately 600 AER's that were in the
Agency's possession as of June 7, 1996, to describe patterns associated with these
reports. A review of the demographic information showed that in over half of the reported
adverse events, the injured party was under 40 years of age. Almost 75 percent of the
adverse events were reported to occur in females, often using products promoted for weight
loss (62 FR 30683). About 59 percent of the adverse events were reported to occur within 4
weeks of starting to use the product. About 14 percent of the reported adverse events
occurred on the first day of using the dietary supplement and, in a few cases, on the
initial use (62 FR 30684). Overall, the reported signs and symptoms associated with these
AER's included those in which clinically serious events occurred, including heart attack,
stroke, psychoses, seizure, and in a few cases, death, as well as those with less clinical
significance, including rapid and irregular heart rhythms, increased blood pressure,
anxiety, nervousness, tremor, hyperactivity, and insomnia (62 FR 30683).
The Agency recognized that these reports could be indicative of early warnings of
serious cardiovascular or nervous system risks if product use were to continue. Notably,
the information from these adverse events revealed consistent patterns of signs and
symptoms in both healthy individuals and in those with underlying diseases or conditions.
Many of these reported signs and symptoms occurred in young adults who generally would not
have been expected to be at high risk for such conditions (e.g., heart attack and stroke).
Included were the deaths of two young adult males in which the medical examiners
attributed the cause of death to ephedrine toxicity (ARMS Nos. 10862 and 11134 at 62 FR
30720 and 30722, respectively). In some cases, particular events appeared to reflect
individual sensitivities related to dose levels, frequency, or duration of use of
ephedrine alkaloids (62 FR 30684).
As depicted in Chart C, the ephedra AER's generated an important "signal",
but were just one small component (the "tip of the iceberg") of FDAs
overall analysis of the potential public health risk associated with this product. To
better understand the nature and types of products associated with these AER's, FDA
conducted a review of the marketplace (62 FR 30679). Over a two-year period, FDA collected
and analyzed over 25 dietary supplement products labeled as containing a known source of
ephedrine alkaloids. FDA also searched the scientific literature for relevant clinical
studies, case reports, and the expected physiologic and pharmacologic effects. In
addition, FDA also convened an ad hoc working group of its Food Advisory Committee
(Working Group) and its Food Advisory Committee to consider the public health problems
associated with the use of ephedrine alkaloid-containing dietary supplements (62 FR
30680). In the proposed rule, FDA requested comments containing data, particularly
clinical data, on the safety of the use of ephedrine alkaloids in dietary supplements. (62
As noted above, while the AER's served as the warning signal of potential hazard
associated with the use of dietary supplements containing ephedrine alkaloids, the
Agency's evaluation of those hazards was comprised of multiple sources of scientific
information. This evaluation included the AER's, a search of the scientific literature,
published case reports, controlled clinical studies, and published reports of adverse
events associated with traditional uses of ephedrine alkaloids. All of these sources of
scientific information revealed a consistent pattern of cardiovascular and nervous system
effects associated with ephedrine alkaloids. That view was affirmed by FDAs Food
Mr. Chairman, thank you for the opportunity to participate in this public dialogue on
passive spontaneous reporting systems. It is my hope that through this forum, you, Members
of the Committee, and the public will appreciate both the value and the challenges these
To effectively provide us with an early warning signal as to possible public health
dangers associated with a given product, these systems need to be healthy. To achieve and
maintain healthy systems requires the computer infrastructure to support the data, and
sufficient staff with the clinical expertise to review and analyze the data. In addition,
it must be recognized that these adverse event reports are but one piece of a
postmarketing/risk assessment process. Health care providers, manufacturers, and the
individuals must each take responsibility for the contribution they must make to ensure
FDAs passive reporting systems continue to provide the value they add to a broader
postmarketing surveillance system.
I will be happy to answer any questions you may have.
Spontaneous reporting systems for blood and blood components
The blood bank and source plasma industry submits the majority of error and accident
reports received by the Center for Biologics Evaluation and Research (CBER). Most of these
reports relate to donor suitability. A proposed rule that published in 1997 would expand
the reporting requirement for licensed facilities to include unlicensed blood
establishments and transfusion services.
When a blood transfusion (or blood collection) complication is confirmed to be fatal,
it must be reported to FDA within 7 days. This information is used for risk assessment and
communication of risk to blood establishments, transfusion services, and physicians.
Adverse events associated with therapeutic plasma-derivative products (such as hemoglobin)
are reported in the same way as adverse events associated with drugs and other therapeutic
Spontaneous reporting systems for vaccines
Vaccine Adverse Event Reporting System (VAERS)
Postmarketing surveillance for vaccines is handled by the Vaccine Adverse Event
Reporting System (VAERS), a system independent of other FDA spontaneous reporting systems.
Established in 1990, VAERS is jointly managed by FDA (CBER's Division of Biostatistics and
Epidemiology) and Centers for Disease Control and Prevention (Vaccine Safety Activity,
National Immunization Program). Representatives of both agencies oversee data processing
and database management performed by a contractor.
VAERS receives 11,000 to 12,000 reports per year. Approximately 15 percent of the
reports describe a serious event, defined as either fatal, life-threatening, or
resulting in hospitalization or permanent disability. Selected reports of serious events
and all reports of fatalities are followed up individually by a health professional, and
autopsy reports, as well as other medical records are retrieved when available. Medical
staff carefully monitor trends in adverse event reporting for vaccines, with particular
attention to newly licensed vaccines. In addition to monitoring reports according to
vaccine type, reports are monitored according to the vaccine lot.
Spontaneous reporting systems for devices
Manufacturer and User Device Experience (MAUDE) Database
In 1984, FDA implemented the Medical Device Reporting (MDR) regulation, which required
manufacturers to report device-related adverse events to FDA. In 1990, the Safe Medical
Device Act (SMDA) amendments expanded FDAs authority by requiring that user
facilities (e.g., hospitals and nursing homes) report device-related serious injuries to
the manufacturer and device-related deaths to the manufacturer directly to FDA. The Agency
receives approximately 80,000 to 85,000 device-related adverse event reports every year.
The bulk of the reports are from manufacturers, with user facilities submitting only about
5,000 of this total. The Manufacturer and User Device Experience (MAUDE) database,
established in 195 to support the SMDA, contains approximately 300,000 reports. Another
500,000 reports are in the pre-1995 database.
When received, reports are first triaged by medical professionals. In general, the
criteria for taking action relate to the unexpectedness and seriousness of the event, the
vulnerability of the population affected, and the preventability of the event. Reports
that involve pediatric death, explosion, and/or multiple injuries from one device, are
sent immediately to supervisors of the report review staff for evaluation and further
action if necessary. All reports are entered into the MAUDE database, subjected to quality
control procedure, and then sent to the clinical analysts for review within 48 hours of
receipt. Clinical analysts review and assess the adverse event reports. Each analyst is
responsible for products within a specific medical specialty or for products that have
common design or material features. Here, as with drugs and biological products, the
analysts experience and familiarity with the products play a significant role in the
evaluation of these reports.
Alternative Summary Reporting
To evaluate more effectively the large number of medical device reports, FDA has
initiated a risk-based alternative reporting system summary reporting.
Products approved for summary reporting are well known with well-documented adverse event
histories. This approach consists of the periodic submission of adverse event data in
tabular format and provides significant economies for both the device industry and FDA. In
the past year, FDA received approximately 30,000 reports in summary format.
Spontaneous reporting systems for cosmetics and foods
Cosmetic Adverse Reaction Monitoring Database (CARM)
The CARM program was initiated in the Office of Cosmetics and Colors, CFSAN, in 1993.
This passive program collects consumer adverse reaction reports received by FDA
Headquarters, FDA District or Field Offices, and the MEDMEDWATCH program. CARM program information is monitored as it is received for
serious adverse reactions that may require immediate follow-up. The CARM computer database
is updated quarterly to add reports received by FDA field offices to those received at the
Office of Cosmetics and Colors. Typically, FDA headquarters will receive about 125-150
consumer complaints into a computer database to facilitate review and evaluation. A CARM
review Committee periodically meets and evaluates adverse reaction summary reports for
evaluation and possible follow-up actions. The Committee includes compliance staff, a
toxicologist, a cosmetic chemist, and program management staff. CARM program follow up
action may include requesting field support through inspections, sample collections and
consumer interviews. Annual CARM summary reports are available for public release and are
provided to the cosmetic industry.
Spontaneous reporting systems for veterinary products
Postmarketing surveillance for veterinary products is handled by the Adverse Drug
Events (ADE) database, a system independent of other FDA spontaneous reporting systems.
The ADE database receives 4,000 to 5,000 reports per year. The bulk of the reports are
from manufacturers. All reports are entered in the ADE database. Medical staff track
adverse events, with particular attention to reported adverse reactions that are not in
product labeling. Medical staff will then often meet with manufacturers to discuss label
changes based on new adverse reactions or product defects. Label changes are suggested if
Adverse Reaction Monitoring System
The ARMS system was originally established in 1985 to collect and evaluate potential
adverse effects to food and color additives, such as aspartame, monosodium glutamate
(MSG), and sulfites. Its use was later expanded to cover other specific food products.
ARMS is a form of passive surveillance that is designed as a sentinel system to identify
specific areas for focused clinical investigations that can evaluate associations between
food and color additives and adverse events. The reports, which tend to be acute in nature
and related to food allergies/intolerance, or microbiological infections, are classified
by severity of the reaction and by the frequency and consistency of the association with
ingestion of the product of interest.