INTRODUCTION
Mr. Chairman and Members of the Committee, I am Susan Ellenberg, Ph.D., Director of the
Division of Biostatistics and Epidemiology in the Center for Biologics Evaluation and
Research (CBER) of the Food and Drug Administration (FDA or the Agency). I appreciate the
opportunity to discuss the Vaccine Adverse Event Reporting System (VAERS), designed to
receive and evaluate reports of adverse events following vaccinations. As requested by the
Committee, I will provide an overview of the system and the evaluation and review of the
information that is obtained through these reports.
THE IMPORTANCE OF VACINE SAFETY
Vaccines are among the most significant public health interventions of all time, and
have been responsible for saving millions of lives and preserving health worldwide.
Nevertheless, like all other medical products, vaccines are not entirely risk-free. While
serious complications are extremely rare, they can occur. Since there is virtually
universal exposure of our population to vaccines, it is important to identify even these
very rare adverse reactions. Vaccines are unique in that they are administered to healthy
individuals, often children, and in some instances are required by State law. The very
highest standards of safety in these products, therefore, are required.
The National Childhood Vaccine Injury Act
In recognition of the importance of vaccine safety, the National Childhood Vaccine
Injury Act of 1986 (NCVIA), 42 U.S.C. � 300aa-1 et seq., as amended, requires each health
care provider and vaccine manufacturer to report to the Department of Health and Human
Services (DHHS) specific adverse events listed in the Vaccine Injury Table following the
administration of vaccines. 42 U.S.C. � 300aa-25. The Vaccine Injury Table is a table of
vaccines and a list of injuries, disabilities, illnesses, conditions and deaths for which
compensation may be provided under the NCVIA. 42 U.S.C. � 300aa-14. FDA has implemented
regulations that clarify the broader responsibilities of vaccine manufacturers, who are
required to report every adverse event of which they learn, regardless of the type of
event (i.e., including those not in the Vaccine Injury Table). 21 C.F.R. � 600.80
The NCVIA led to the creation of a unified national system to collect, manage and
evaluate these adverse event reports. This system, initiated in 1990 and jointly managed
by FDA and the Centers for Disease Control and Prevention (CDC), is VAERS. VAERS receives
reports from vaccine manufacturers, private practitioners, state and local public health
clinics, and vaccinees themselves (or their parents or guardians). It is similar in intent
and operation to surveillance systems for other types of FDA regulated products maintained
by the FDA and to safety surveillance programs in other countries. VAERS accepts all
reports of suspected adverse events after administration of any U.S. licensed vaccine.
POST-MARKETING SURVEILLANCE SYSTEMS
VAERS is a "passive" surveillance system. This means that it relies on health
professionals, patients or guardians to submit reports of adverse reactions following
vaccination. (An "active" surveillance system, in contrast, would follow all
individuals in a defined population to determine their responses to vaccination.) To
encourage reporting of any possibly vaccine-induced adverse event, the criteria for
reporting to VAERS are non-restrictive. In effect, the system accepts and includes any
report submitted, no matter how tenuous the possible connection with vaccination might
seem.
These types of systems are essential to the discovery of potential rare adverse
consequences of medical products that may not become evident until millions of people have
been exposed to them. While they are critical to FDA's post-marketing surveillance, there
are important limitations to the interpretation of the data, however, as discussed below.
OVERVIEW OF VAERS ACTIVITIES
VAERS receives 11,000 to 12,000 reports per year. (This number does include some
multiple reports of the same incident, most often these are of serious reports.)
Approximately 15 percent of the reports describe a "serious" event, which
is considered to be either fatal, life-threatening, or resulting in hospitalization or
permanent disability. Most of the remaining reports describe self-limited, transient
events such as injection site reactions, irritability, prolonged crying and fever.
All reports are entered into a computer database. Selected reports of serious events
and all reports of fatalities are followed up individually by a health professional.
Autopsy reports and other relevant medical records are sought and retrieved for review.
Medical staff carefully monitor individual reports and trends in adverse event reporting
for vaccines, with particular attention to newly licensed vaccines.
VAERS data are available to the public through the National Technical Information
Service and also through requests to FDAs Freedom of Information office. Patient
identifiers are removed from all data provided to the public. General information and the
VAERS form itself are available on the VAERS Internet website. The website address is:
www.fda.gov/cber/vaers.html.
OBJECTIVES OF VAERS
Spontaneous report-based surveillance programs, such as VAERS, perform a critical
function by generating signals of potential problems that may warrant further
investigation. As such, VAERS is the "front line" of national vaccine safety
surveillance. It is especially valuable in assessing the safety of newly marketed
vaccines. Careful review of reports during the initial months following licensure can
provide additional assurance about the safety of a new vaccine, uncover previously
unexpected events which occur when a vaccine is used in a more diverse population than was
studied in clinical trials or rapidly identify potential problems not observed
pre-licensure. Such a review was conducted several years ago by FDA investigators for
reports of adverse events in infants following hepatitis B vaccine. This comprehensive
review concluded that no serious events likely attributable to the vaccine had emerged in
the first few years following the recommendation for universal infant immunization.
Although VAERS has methodological limitations inherent in passive surveillance systems,
VAERS is essential to the U.S. vaccine safety monitoring system. It is the only
surveillance system which covers the entire U.S. population and includes the largest
number of case reports of events temporally associated with vaccination in the U.S. It
provides timely availability of data from a geographically diverse population, allowing
rapid detection of possible new, unusual or rare adverse events. Such detection generates
hypotheses that may then be tested in other databases.
Based on careful review, analysis and further investigation of spontaneous reports, FDA
can initiate various actions: manufacturers labeling or packaging change(s),
conducting or requesting manufacturer-sponsored post-marketing epidemiological
investigations (hypotheses testing in more rigorous databases ); issuing a Safety Alert or
"Dear Health Professional" letter, inspecting manufacturers
facilities/records, or working with a manufacturer regarding possible withdrawal of
vaccine from the market (for safety or efficacy reasons). Keeping vaccine labeling/package
inserts up-to-date is an ongoing, dynamic process that depends on new information gleaned
from spontaneous adverse event reports as well as other sources. Dissemination of
safety-related information to health care professionals and the public is an important
health goal of post-marketing surveillance.
LIMITATIONS OF VAERS
While assessment of VAERS data is a critical first step in identifying potential new
information about the safety of vaccines, it is important to recognize that VAERS data
alone are often inadequate for drawing firm conclusions or providing a basis for
regulatory actions. Many reports omit important data and/or contain obvious errors that
may not be easily identifiable or correctable. Multiple vaccines are frequently
administered simultaneously, according to currently recommended vaccine schedules, making
it difficult or impossible to determine which (if any) of the vaccines administered was
the possible cause of the event. The extent of under-reporting of events occurring after
vaccination is unknown, and the number of individuals in subgroups of interest (for
example, infants) receiving the vaccine during specific time intervals is not known, so
that incidence rates cannot be calculated. In addition, because VAERS accepts and
encourages reports of all temporal associations, regardless of the rationale for the
vaccine being the cause of the outcome reported, there is also "over-reporting"
since many events reported, and entered in the database, are most likely not attributable
to vaccination.
Probably the most important limitation of VAERS, as it is for any passive reporting
system, is its inability to establish causality for most reports it receives. Adverse
events occurring in unvaccinated individuals are not reported, so there is no
"control group" to study. Most of the types of serious adverse events reported
to VAERS can occur in unvaccinated as well as vaccinated individuals. Without an
unvaccinated group it is usually impossible to assess whether the number of reported
events is different from the number that would have been observed in the absence of
vaccination.
With virtually universal childhood immunization, beginning at birth or shortly
thereafter, any adverse medical event in a child will "follow" vaccination, and
some of these will coincidentally follow within a few days of a vaccination. Thus,
even if a vaccine is not the cause of certain rare medical problems, it is a certainty
that some number of these events will occur within a short interval following a
vaccination. For this reason, the fact that an eventeven a very serious event such
as a deathoccurs shortly after a vaccine has been administered cannot by itself lead
to the conclusion that the event was caused by the vaccine.
An adverse event can be causally attributed to a vaccine more readily if:
1. The event conforms to a specific clinical syndrome whose association with
vaccination has strong biologic plausibility (e.g., anaphylaxis).
2. A laboratory result confirms association (e.g., isolation of vaccine strain
varicella vaccine from skin lesions of a patient with rash).
3. The event recurs on re-administration of vaccine ("positive
rechallenge.").
4. A controlled clinical trial or well-designed epidemiological study shows greater
risk of adverse events among vaccinated than unvaccinated (control) groups.
Because few of the serious adverse events reported to VAERS meet any of the first three
criteria (one such example, however, is described below), and because clinical trials are
almost always too small to provide useful information on rare events, methodological more
rigorous epidemiological studies must be conducted to assess causality for most serious
adverse events that are investigated. A determination that the vaccine caused the
post-vaccination event usually cannot be made on the basis of information acquired from
individual VAERS reports.
VACCINATION AND SIDS
Sudden Infant Death Syndrome (SIDS) exemplifies the problem with interpreting VAERS
data. About 150 deaths a year are reported to VAERS. Most of these are of infants under
one year of age; of these, most are diagnosed as SIDS. The reported time from vaccination
until death varies from a few hours to many weeks or even months. In most cases multiple
vaccines are involved, consistent with recommended immunization schedules. Because SIDS
occurs during the first year of life both in the absence and presence of vaccination, one
cannot presume a causal connection if SIDS follows shortly after vaccination. In fact, one
can predict that such events would occur, even in the absence of a causal connection,
because virtually all infants (approximately four million live births per year in the
U.S.) receive vaccines on multiple occasions during the first year of life and because
SIDS occurs at the relatively high rate of somewhat less than one per thousand live births
in the U.S.
In response to public concerns arising in the early 1980s about the safety of another
vaccine, the DTP (diphtheria, tetanus, pertussis) vaccine, the National Institutes of
Health's National Institute of Child Health and Human Development investigated the
question of the association between SIDS and DTP in a large case-control study. This study
did not support the hypothesis that DTP vaccine caused SIDS; it demonstrated a lowered
risk for SIDS in children receiving DTP vaccine. FDA continues to review each death,
including all SIDS deaths, reported following administration of DTP vaccine.
MULTIPLE SCLEROSIS
Recent attention has been given to the possibility that vaccination with a hepatitis B
vaccine increases the risk for developing multiple sclerosis (MS). While we cannot say
with absolute certainly that the vaccine has never caused a case of MS, some temporal
associations are expected because hepatitis B vaccine is administered to the same age
groups where symptoms of MS first occur. Since 1990, VAERS has received 76 U.S. reports of
MS following vaccination with hepatitis B vaccine. These reports are spread fairly evenly
over the years. CDC has undertaken a further prospective study of the possible association
between demyelinating disease (neurological diseases) and the hepatitis B vaccine.
VACCINE SAFETY DATALINK
As noted previously, when review of VAERS data identifies potential new
vaccine-associated events, the hypothesis of causation must be further investigated in
more rigorously controlled studies. Such studies can be performed by CDCs Vaccine
Safety Datalink (VSD), a computerized medical record linkage system of patients enrolled
in four health maintenance organizations, where causality may be more rigorously
evaluated. FDA has worked with the VSD to address a variety of concerns, some of which
have arisen from VAERS reports.
For example, FDA's review of adverse events reported in infants following receipt of
hepatitis B vaccine, noted above, revealed an apparent difference between two brands of
this vaccine with regard to reporting rate (i.e., the number of reports divided by number
of doses distributed). Nothing in the product content or manufacturing processes provided
a likely explanation for this difference. Because of the limitations of data in
spontaneous reporting systems like VAERS, FDA believed it was essential to study this
issue further to determine whether or not the difference was real. Data from VSD sites
that had used both vaccines were reviewed. These data, which provided a true event rate in
a defined population, showed similar rates of adverse events for both vaccine brands.
CONTRIBUTIONS OF VAERS DATA TO UNDERSTANDING
VACCINE SAFETY
New Reactions
Several investigations of VAERS data have uncovered previously unrecognized problems
that may occur rarely in vaccine recipients. FDA investigators noted occasional instances
of life-threatening thrombocytopenias (low platelet counts) following the administration
of MMR (measles, mumps, rubella) vaccine, a previously unappreciated level of severity of
a known side effect. Other FDA investigators documented a series of cases in which hair
loss followed immunizations (primarily hepatitis B vaccine), a rare effect not previously
reported. Because some of these cases exhibited "positive rechallenge," as
defined earlier, there is a greater level of confidence that these outcomes truly may have
been caused by the vaccine. In another study, FDA staff identified a series of cases of
severe injuries resulting from vaccination-induced fainting or syncope. These outcomes did
not appear related to any specific vaccine, but were most probably attributable to the act
of vaccination itself.
Sometimes VAERS data may provide the useful and reassuring information that new
problems have not been identified after additional experience with a vaccine, as in the
previously noted report on hepatitis B vaccine in infants.
Trends in Reporting
VAERS data also have been used to compare reporting patterns over time and investigate
changes in reporting rates that might be due to changes in vaccine practices. For example,
CDC epidemiologists reviewed reports of fever, seizures, and hospitalizations following
administration of a newly licensed combination of diphtheria, tetanus and acellular
pertussis vaccine (DtaP). The rate of such reports was about one-third lower than the
reporting rate following the standard DTP vaccine, consistent withand confirming in
the context of general practicethe safety findings of the pre-licensure clinical
trials.
CONCLUSION
Vaccine safety is the subject of numerous initiatives within the Public Health Service,
and FDA participates in a variety of cross-agency efforts in this area, including the
vaccine Inter-Agency Group coordinated by the National Vaccine Program Office, the Vaccine
Safety Subcommittee of the National Vaccine Advisory Committee, and the Advisory
Commission on Childhood Vaccines. FDA sends liaison members to other Public Health Service
agency advisory groups.
FDA evaluates the risks and benefits, both known and potential, for all FDA regulated
medical products. Hepatitis B vaccines have demonstrated clear and major benefits in
reducing transmission of hepatitis B infections. Such infections have been known to cause
serious liver disease and primary liver cancer. Thus at present, we have well documented
benefits and little in the way of verified serious risks. The Agency will continue to
monitor and investigate the serious adverse reports received on hepatitis B vaccines and
all vaccines.
Vaccine safety is a high priority of FDA and the Agency considers all of its safety
programs, including VAERS, as critical to carrying out the goal as stated in the NCVIA. 42
U.S.C. � 300aa-1. The goal is to achieve "optimal prevention of human infectious
diseases through immunization and to achieve optimal prevention against adverse reactions
to vaccines." FDA continues to work towards this goal.
Thank you for this opportunity to discuss the VAERS system and its importance to
vaccine safety.