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Statement on Hepatitis B Vaccine by Susan S. Ellenberg, Ph.D.
Director, Biostatistics & Epidemiology Division
Center for Biologics Evaluation and Research
Food and Drug Administration
U.S. Department of Health and Human Services

Before the House Committee on Government Reform, Subcommittee on Criminal Justice, Drug Policy and Human Resources,
May 18, 1999


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.


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.


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.


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 FDA’s 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.


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.


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 event—even a very serious event such as a death—occurs 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.


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.


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.


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 CDC’s 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.



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 with—and confirming in the context of general practice—the safety findings of the pre-licensure clinical trials.


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.

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