Assessing Adverse Events Associated with Vaccines: A Workshop Summary (1994c).

DIFFICULTIES IN DETECTING ADVERSE EVENTS FOLLOWING VACCINATION2

A number of factors make it difficult to detect adverse events associated with vaccination and to determine whether the event is causally associated with the administration of a vaccine: (1) the need to study multiple exposures and multiple outcomes, (2) the lack of unique vaccine-associated syndromes, making it difficult to establish causality, (3) the need for large sample sizes and the lack of large computerized immunization databases with individual level data including vaccine lot number, (4) brief exposure periods for each individual, (5) high vaccination coverage makes unvaccinated individuals highly selected.

Individuals are often given several vaccines simultaneously, making it hard to assess which vaccine exposure might be causing an adverse event. In addition, several possible adverse events can occur following a single vaccination. Traditional public health surveillance measures are usually aimed at detecting a single specific disease outcome or event following exposure to a single agent or disease entity (for infectious diseases, this follows exposure to an etiologic factor such as human immunodeficiency virus). Postmarketing surveillance of vaccines, in contrast, must be structured to detect multiple outcomes, should they occur, following multiple exposures. In addition, surveillance for adverse events associated with vaccination requires the ability to detect both an increase in the frequency of previously known adverse events and the emergence of new, unanticipated adverse events. It is difficult to detect both types of events with a single surveillance system. Traditionally, separate surveillance systems have been established for each purpose, each optimized for its particular objectives.

The lack of a unique laboratory diagnosis or unique clinical syndrome for most of the adverse outcomes investigated in relation to vaccination also makes it difficult to detect adverse events following vaccination. At present, no laboratory diagnosis or clinical description can differentiate a seizure that is caused by a vaccination, for example, from one that is caused by another factor. The lack of a unique syndrome or diagnosis makes it difficult to assess whether the adverse event is coincidental to vaccination (but not caused by it) or a true adverse reaction to the vaccine itself. Most childhood vaccines are given at an

2  

 The material in this section is adapted from a presentation by Robert Chen and from comments by other workshop speakers and participants.



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Vaccine Safety Forum: Summaries of Two Workshops Assessing Adverse Events Associated with Vaccines: A Workshop Summary (1994c). DIFFICULTIES IN DETECTING ADVERSE EVENTS FOLLOWING VACCINATION2 A number of factors make it difficult to detect adverse events associated with vaccination and to determine whether the event is causally associated with the administration of a vaccine: (1) the need to study multiple exposures and multiple outcomes, (2) the lack of unique vaccine-associated syndromes, making it difficult to establish causality, (3) the need for large sample sizes and the lack of large computerized immunization databases with individual level data including vaccine lot number, (4) brief exposure periods for each individual, (5) high vaccination coverage makes unvaccinated individuals highly selected. Individuals are often given several vaccines simultaneously, making it hard to assess which vaccine exposure might be causing an adverse event. In addition, several possible adverse events can occur following a single vaccination. Traditional public health surveillance measures are usually aimed at detecting a single specific disease outcome or event following exposure to a single agent or disease entity (for infectious diseases, this follows exposure to an etiologic factor such as human immunodeficiency virus). Postmarketing surveillance of vaccines, in contrast, must be structured to detect multiple outcomes, should they occur, following multiple exposures. In addition, surveillance for adverse events associated with vaccination requires the ability to detect both an increase in the frequency of previously known adverse events and the emergence of new, unanticipated adverse events. It is difficult to detect both types of events with a single surveillance system. Traditionally, separate surveillance systems have been established for each purpose, each optimized for its particular objectives. The lack of a unique laboratory diagnosis or unique clinical syndrome for most of the adverse outcomes investigated in relation to vaccination also makes it difficult to detect adverse events following vaccination. At present, no laboratory diagnosis or clinical description can differentiate a seizure that is caused by a vaccination, for example, from one that is caused by another factor. The lack of a unique syndrome or diagnosis makes it difficult to assess whether the adverse event is coincidental to vaccination (but not caused by it) or a true adverse reaction to the vaccine itself. Most childhood vaccines are given at an 2    The material in this section is adapted from a presentation by Robert Chen and from comments by other workshop speakers and participants.

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Vaccine Safety Forum: Summaries of Two Workshops age when medical problems due to genetic or congenital factors are first manifesting themselves. Therefore, it is difficult to assess whether these medical problems are caused by the vaccine or are coincidental to vaccine administration. Often, it is not possible to assess how many individuals have been given a vaccine of interest, which creates an additional surveillance difficulty. This information is needed to determine what proportion of people receiving the vaccine are experiencing adverse events. Usually, the only data easily available are the number of doses of vaccine distributed, not the number of doses actually administered at any given time. In addition, for individuals who have had an adverse reaction to vaccination, the vaccine lot and manufacturer may not be known, making it difficult to trace potential problems with a particular lot or batch of vaccine. Another challenge to detecting adverse events is that only a few doses of a single vaccine are usually given to an individual. If the risk of an adverse event is dose related, the likelihood that an adverse reaction occurs after vaccine administration is therefore much lower than after the administration of drugs because drugs are given several times a day for a period of weeks or months. In addition, large populations are needed to conduct epidemiologic studies designed to detect rare adverse events. Studying such large populations can be difficult to do in a timely manner and can be very expensive. Finally, the fact that large numbers of children in the United States receive vaccinations during childhood presents problems in detecting adverse events following vaccination. In particular, it is difficult to find a comparable control population that has not received the vaccine to help assess potential causality and to determine how often adverse events occur in the absence of vaccination. Those individuals who, voluntarily or otherwise, do not receive vaccines may be different in other respects from those who do. They therefore are not a suitable control population. For example, children who are not vaccinated may be in poorer health, may receive different types of health care in general, or may be part of a restricted gene pool if they are members of religious groups that decline vaccines. In addition, the unvaccinated population may not be large enough to allow for the study of background rates of rare medical events. Although some researchers express ethical concerns about conducting a controlled trial that would require large numbers of individuals not to receive a vaccine from which they might benefit, some parents and consumers express ethical concerns about assuming that the benefit of a tested vaccine will outweigh its risks.