Participation in Clinical Trials

A participant commented that it has been relatively easy to recruitsubjects for vaccine trials in the United States because vaccinesare expensive and the costs to individuals in the trial were covered.She speculated that universal access to vaccination might have anadverse impact on the motivation to participate in vaccine trials.

Ethical Issues

Several participants expressed worries about the ethical consequencesof conducting studies with placebo-treated controls to assess theadverse consequences of vaccines (which, because the outcomes arerare, require large sample sizes). Efficacy issues can usually beanswered with much smaller sample sizes. Waiting to accrue sufficientpatients to detect rarely occurring adverse outcomes necessarilymeans that thousands of placebo-treated control patients will bedenied the established benefits of the vaccine. However, if sucha study were conducted, vaccinated children would potentially beat risk for rarely occurring but serious adverse events. (See thediscussion regarding unvaccinated controls in the next section.)

There was a discussion on the social problems of conducting clinicaltrials in traditionally underserved or neglected populations, suchas inner cities. Recent experience indicates that these populationsare suspicious of the true intent of the study, believing that itis a trial of a harmful substance or procedure.

Clinical trials for evaluating vaccine efficacy generally do notinclude sufficient sample sizes to permit adequate evaluations ofthe risk of adverse reactions. Participants expressed dismay thatpostmarketing studies of vaccines are generally not randomized controlledtrials. The role of clinical trials for assessing adverse reactions is limited.

OTHER TOPICS

Unvaccinated Controls

Discussion arose about the issue of the lack of unvaccinated controlsin the studies under consideration. Some participants felt that atrue control group in a study of vaccines and adverse events wouldconsist of never-vaccinated children (whereas now, control groupsoften consist of children who had not been vaccinated recently). It would then be possible to look at the frequencies of adverseevents and disease in these children in comparison with the frequencies



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Research Strategies for Assessing Adverse Events Associated withVaccines:: A Workshop Summary Participation in Clinical Trials A participant commented that it has been relatively easy to recruitsubjects for vaccine trials in the United States because vaccinesare expensive and the costs to individuals in the trial were covered.She speculated that universal access to vaccination might have anadverse impact on the motivation to participate in vaccine trials. Ethical Issues Several participants expressed worries about the ethical consequencesof conducting studies with placebo-treated controls to assess theadverse consequences of vaccines (which, because the outcomes arerare, require large sample sizes). Efficacy issues can usually beanswered with much smaller sample sizes. Waiting to accrue sufficientpatients to detect rarely occurring adverse outcomes necessarilymeans that thousands of placebo-treated control patients will bedenied the established benefits of the vaccine. However, if sucha study were conducted, vaccinated children would potentially beat risk for rarely occurring but serious adverse events. (See thediscussion regarding unvaccinated controls in the next section.) There was a discussion on the social problems of conducting clinicaltrials in traditionally underserved or neglected populations, suchas inner cities. Recent experience indicates that these populationsare suspicious of the true intent of the study, believing that itis a trial of a harmful substance or procedure. Clinical trials for evaluating vaccine efficacy generally do notinclude sufficient sample sizes to permit adequate evaluations ofthe risk of adverse reactions. Participants expressed dismay thatpostmarketing studies of vaccines are generally not randomized controlledtrials. The role of clinical trials for assessing adverse reactions is limited. OTHER TOPICS Unvaccinated Controls Discussion arose about the issue of the lack of unvaccinated controlsin the studies under consideration. Some participants felt that atrue control group in a study of vaccines and adverse events wouldconsist of never-vaccinated children (whereas now, control groupsoften consist of children who had not been vaccinated recently). It would then be possible to look at the frequencies of adverseevents and disease in these children in comparison with the frequencies

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Research Strategies for Assessing Adverse Events Associated withVaccines:: A Workshop Summary in those who had been vaccinated. This might be particularly relevantin studying adverse events with long latencies from the time of vaccination.There was concern by some that unvaccinated individuals are so differentfrom vaccinated individuals that these differences cannot be controlledfor; that is, completely unvaccinated individuals might possess otherhealth or socioeconomic traits if they are from a population thatdoes not believe in traditional medical treatments, or they mightrepresent a limited gene pool if the population consists of a longstanding,religious sect. One participant argued that comparison with unvaccinatedcontrols might make vaccines look more beneficial than they are,because those who are not vaccinated are more likely to be underprivilegedor have more diseases or disorders for other reasons. The decreasedincidence of SIDS following immunization with DPT is an example ofthis (Institute of Medicine, 1991). Others noted that there are individualswho would be willing to participate, or have their children participate,as unvaccinated controls, and it was suggested that statistical methodscould be used to address the problem of the self-selection of thegroup. Still others believed that the number of unvaccinated subjectsis too low for detection of rarely occurring adverse events. One participant noted that religious groups that decline vaccinationhave occasionally been studied during acute outbreaks of diseaseand speculated that it might be possible to work with them in attemptingto find the background rates of particular adverse events in unvaccinatedchildren. It was noted that the possible problem of a restrictedgene pool would have to be taken into consideration, particularlyfor certain adverse events. Background Incidence Rates The need for more complete information on the background incidencerates of the adverse events was discussed. It was suggested thatvital statistics data or other studies of infant mortality be exploitedfor ecologic correlations, that is to look for changes in mortalityin periods before and after new vaccines are introduced. Some participantsthought that this was a fairly crude approach to the subject andthat it should be looked at in great depth. It was noted that a vaccinewould have to account for a large proportion of deaths (and thereis no reason to believe that any vaccine does) to show a differenceusing crude mortality data. In addition, one participant thoughtthat there would be too much seasonal and other variation for theinfant mortality approach to be helpful unless a concurrent, controlledstudy were to be done. It was noted that the question of background incidence rates wasalso of concern to the IOM vaccine-adverse event committees (Instituteof Medicine, 1991, 1994a). It may be possible to derive reasonablyaccurate rates for such conditions as GBS and multiple sclerosisin adults, but when considering such conditions as encephalopathyand encephalitis in children, the conditions are

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Research Strategies for Assessing Adverse Events Associated withVaccines:: A Workshop Summary diagnosed so differently among various studies that the terms becomealmost meaningless. People must agree to use the same diagnosticcriteria for the same conditions. Much education is necessary toget good background information. Some felt that this was possibleand that having standard definitions then assumes great importance.It was noted that even neurologists have not reached consensus onthe definitions of encephalopathy and encephalitis. However, in responseto the question of whether swine flu vaccine can cause GBS, a groupof neurologists was brought together to develop a definition thathas been generally accepted (Asbury and Cornblath, 1990; Asbury etal., 1978). Adverse Events with Long Latencies Previous discussions examined the potential utility of case reportsin assessing causality. This is particularly true for assessing thecausalities of adverse events that occur shortly after vaccination.Although anaphylaxis, for example, can occur without an obvious cause,the relation to vaccination in an individual case is easy to determineif it occurs within minutes of exposure to the antigen. In contrast,problems of assessing causality for adverse events with long latenciesfrom the time of exposure are many. The many discussions in the publishedliterature regarding the British National Childhood EncephalopathyStudy (NCES), including a recently released IOM report by the committeeto Study New Research on Vaccines (Institute of Medicine, 1994),show the lack of agreement in the scientific community on how bestto address these questions. A participant noted that events with long latencies have traditionallybeen studied by the case-control method (as was done in the NCES)and that this will probably continue to be the primary way in whichthey are investigated. The selection of controls, however, is veryimportant. If the coverage rate for the vaccine is high, the requiredsample size could be large. It was suggested that it might be useful to identify children whoparticipated in pre-marketing trials and follow them over the longterm.This is not currently done routinely, but it might be a worthwhileeffort, even though it would be difficult. Another participant commentedthat the unexposed group in a randomized trial will, if the vaccineis licensed and in general use in a few years, most likely becomevaccinated. In terms of looking at long latencies, there is not muchdifference between those who received a vaccine 18 years earlierand those who received it 21 years earlier. Subacute sclerosing panencephalitis (SSPE) was mentioned as an exampleof the difficulty of dealing with long-latency events. A participantcommented on SSPE and multiple sclerosis; in the 1960s, both werebelieved to be associated with measles disease. Since the adventof the measles vaccine, there has been a 90 percent decrease in theincidence of SSPE, whereas there has been no change in the incidenceof multiple sclerosis. A participant commented that

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Research Strategies for Assessing Adverse Events Associated withVaccines:: A Workshop Summary the question now is not whether the measles vaccine can prevent SSPE;obviously it can, by preventing disease from wild-type measles virusinfection. Still in question is whether there are rare cases of SSPEcaused by the vaccine. Although technical advances are making itpossible to isolate virus from the brains of patients with SSPE andtype the RNA as being of the vaccine strain or the wild-type, thefailure to isolate vaccine-strain virus does not prove that the vaccinecannot cause SSPE. As was articulated by the IOM committees (Instituteof Medicine, 1991, 1994a) it is impossible to prove a negative. However,typing an isolated virus from a patient with SSPE as vaccine strainwould be important data to suggest that measles vaccine can cause SSPE. This is hypothetical at present. Multifactorial Etiologies Adverse events that are multifactorial in etiology, for example,insulin-dependent diabetes mellitus, provide particular challenges.In these instances, the vaccine might serve as an additional stimulusto a genetic background that predisposes a child toward the condition.It was mentioned that as more and more genes for diseases are identified,more conditions that fall into this category may be identified. Once causality between a condition and a vaccine is established,epidemiologic methods could be used to study why some people whoreceived, for example, influenza vaccine got GBS and others did not.What is different about those who develop the disease or condition?But even if one could identify risk factors for adverse events, itmay not be feasible or practical to screen for them prior to immunization. A participant commented that there are a number of suspicions aboutpredisposing conditions that might be exacerbated by vaccines (forexample, arthritis and hepatitis B vaccine). Such examples shouldbe defined and looked at in LLDBs. It was suggested that generalresearch projects designed primarily to study the pathophysiologyor genetics of conditions such as diabetes might include vaccineissues as part of their study designs. Need for Basic Research A participant stressed that it is important to understand the mechanismsof the adverse events. It would be a mistake to address the problemof safety only from the moment of licensure. Basic laboratory researchon possible immunopathologic or infectious sequelae of vaccines,in addition to surveillance and epidemiologic studies, is needed.