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3 Methodologic Considerations in Evaluating the Evidence
Pages 32-64

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From page 32...
... This chapter outlines the specific questions the committee posed, the types of evidence it identified, its approaches to evaluating reports both singly and collectively, and the nature of the conclusions it felt that logic and evidence permitted. Against this background, details of the analysis and specific conclusions concerning each type of adverse event appear in subsequent chapters.
From page 33...
... When the great majority of the population is exposed, as is generally true for pertussis and rubella vaccines, comparisons between exposed and nonexposed persons become clouded. This is due to the potential for selective factors against vaccination to confound the relation between immunization status and the occurrence of adverse events.
From page 34...
... As in science generally, studies of adverse events following vaccination are not capable of demonstrating a zero effect, that is, that the purported effect is impossible or could not ever occur. Any instrument of observation has a limit to its resolving power, and this is true as well of randomized clinical trials and epidemiologic studies.
From page 35...
... which becomes pertinent only if the ~ v ~ _ ~ ~ 1 - - answer to the first question is affirmative, concerns the proportion of individuals in a specified population who experience the adverse event because of the exposure. The most desirable evidence as a basis for answering this type of question involves knowledge of the rate of occurrence of the event in those who are exposed, the rate in those who are not exposed (the "background" rate of the event in the population)
From page 36...
... A third type of causal question is whether, in a specific instance of exposure and an adverse event, it can be concluded that the event was caused by the vaccine exposure. This question is especially pertinent to those types of adverse events for which case reports constitute a substantial part of the evidence available for review.
From page 37...
... Subsequent chapters of the report summarize the evidence concerning each vaccine-event relation under review and present the committee's conclusions. If the first question (can the vaccine cause the adverse event?
From page 38...
... In fact, since the first reports of serious adverse events following administration of pertussis and rubella vaccines (Madsen, 1933; Modlin et al., 1975) , virtually no placebo-controlled or other experimental
From page 39...
... And although it should be noted for completeness that other experimental approaches, such as formal communitywide comparisons of the impact of vaccination programs, including both beneficial outcomes and adverse events, are applicable in principle, evidence of this type is also generally unavailable. Experiments in Animals: Animal Models In principle, experimental studies in animals allow for both rigid control over vaccine exposure and intensive observation for any adverse events that may follow.
From page 40...
... With respect to rubella, the committee could find no studies of animal models of either the disease or rubella vaccine-related illness that were specific to the adverse events under consideration. The discussion below therefore refers specifically to pertussis.
From page 41...
... Observational studies in humans have been a more useful basis for making judgments about the possibility of causation of adverse events by pertussis and rubella vaccines. (See Appendix C for further discussion of the animal models used to study pertussis and pertussis vaccine.)
From page 42...
... Cohort Studies Cohort studies track groups that are defined by common characteristics, including their exposure status, for example, vaccinated and unvaccinated, at the starting point of observation. The rates of occurrence of adverse events are compared between these groups over time.
From page 43...
... Because the outcomes in question are generally rare, the casecomparison design has more often been used in the investigation of the rare adverse events considered in this report. Case-Comparison Studies Controlled epidemiologic studies in which the subjects are selected in accordance with their disease status, for example, with or without encephalopathy, and investigated to determine their prior histories of exposure, for example, whether or not they had received pertussis vaccine, are termed case-comparison or case-control studies.
From page 44...
... of Great Britain is an example of the case-comparison design applied to the study of rare necrologic events following pertussis vaccination (see Chapter 4 for further details)
From page 45...
... Thus, "information bias" is a concern in case-comparison studies that does not arise in the same way in cohort studies, in which exposure is documented in advance of the adverse event. A number of other sources of bias potentially enter into case-comparison studies, cohort studies, or both.
From page 46...
... To date, such noncontrolled clinical studies provide the only source of information for 7 of the 20 adverse events under review by the committee: in relation to pertussis vaccine, erythema multiforme and other rash, GuillainBarre syndrome, peripheral mononeuropathy, hemolytic anemia, and thrombocytopenia; and in relation to rubella vaccines, radiculoneuritis and other neuropathies, and thrombocytopenic purpura. Searching for Patterns One application of the case reports and case series available concerning a particular adverse event is to seek clinical or epidemiologic patterns within the
From page 47...
... Despite the more than 100 cases abstracted, the committee was not able to identify a specific and consistent syndrome of vaccineinduced encephalopathy, the condition for which this question was considered most worth investigating in this manner. In special circumstances, for example, in the absence of a controlled study or other epidemiologic data and in the presence of supportive clinical evidence, the committee considered that specific reports of an adverse event following vaccination might suggest a biologically plausible relation.
From page 48...
... Causation of the Individual Case Case reports and case series data also bear on the question of causation of an individual case, for example, whether a given adverse event is an allergic response to pertussis vaccine. Individual cases of the adverse event could be examined to determine whether the event occurred in a clear sequence following each pertussis immunization in the series.
From page 49...
... , MSAEFI calculated its incidence rates of adverse events following vaccination on the basis of voluntary reports from physicians, allied health professionals, and others. Being dependent on voluntary reports, MSAEFI is a "passive" surveillance system.
From page 50...
... The validity of a study, which is the focus of this initial assessment, is rarely an absolute judgment but differs by degree for different aspects of the study. Strengths and limitations of individual studies, in various re 3A special note concerning the reporting of incidence rates of adverse events following nertussis immunization is merited.
From page 51...
... When a number of sufficiently similar studies of the same adverse event are available, it is sometimes possible to pool statistical information from
From page 52...
... Considerations in Inferring Causality For each adverse event for which the evidence indicated the presence of an association with vaccine exposure, the committee assessed the applicability of each of six general considerations, patterned after those attributed to Hill (1971~. Reflecting thought about the problem of causal inferences in chronic disease epidemiology that had evolved over several years, Hill proposed the following guidelines for judgment: strength of association, doseresponse relations, temporally correct association, consistency of association, specificity of association, and biologic plausibility.
From page 53...
... The committee, in addition, considered whether the adverse event occurred within a time interval following vaccination that was consistent with current understanding of its natural history. The committee interpreted the lack of an appropriate time sequence as strong evidence against causation, but recognized that insufficient knowledge about the natural history and pathogenesis of many of the adverse events under review limited the utility of this consideration.
From page 54...
... One special consideration in evaluating summary evidence on the relation of adverse events to pertussis or rubella immunization was that of the variation in vaccine composition observed across manufacturers. With respect to the whole-cell pertussis vaccine, for example, the committee recognized that methods of production, seed bacteria, preservatives, and adjuvants used in manufacturing the vaccine have varied substantially over the years (Cox et al., 1987; Ross, 1988)
From page 55...
... What, then, are the implications of these variations in vaccine composition and schedules for the evaluation of vaccine-adverse event associations? With respect to rubella vaccines, rates of arthritis and arthralgia following immunization were found to differ by strain (see Chapter 71.
From page 56...
... The resolution or discriminating capacity of epidemiologic studies could theoretically be increased indefinitely through ever larger study populations. However, there are many constraints on the feasibility of large studies.
From page 57...
... Epidemiologic studies are often designed to provide statistical tests that minimize type I error, the probability that the null hypothesis is falsely rejected. Commonly, such tests are designed so that there is less than a 5 percent chance that the test will incorrectly indicate an association between a vaccine and an adverse event if no association truly exists.
From page 58...
... For individual studies, confidence intervals around estimated results such as relative risks represent a quantitative measure of uncertainty. Confidence intervals present a range of results that, with a predetermined level of probability, include the true relative risk being estimated.
From page 59...
... The fifth category, biologic plausibility, includes background knowledge concerning the pathophysiology of an adverse event, attributes of a particular vaccine, or other biologic information derived from research in such areas as immunology and physiology. Where evidence was available in a particular category, the committee judged whether that evidence was generally supportive or not supportive of causation or whether it was insufficient for a determination.
From page 61...
... 61 ~i, x x x -x o c ~50 ~o o ~ ~ o ~ en ~O C _ ~ ° ~ >to 5 - ~ ~ ~ - ~ ~ ~ ~ _ ~ ~ CJ
From page 62...
... 1984. Adverse Events Following Immunization: Surveillance
From page 63...
... 1986. Adverse Events Following Immunization: Surveillance Report No.2, 1982-1984.
From page 64...
... a whole cell pertussis vaccine combined with diphtheria and tetanus toxoids as a booster in 18- to 24-month old children. Pediatric Infectious Disease Journal 6:352-363.


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