The Childhood Immunization Schedule and Safety Stakeholder Concerns, Scientific Evidence, and Future Studies (2013) / Chapter Skim
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6 Methodological Approaches to Studying Health Outcomes Associated with the Current Immunization Schedule: Options, Feasibility, Ethical Issues, and Priorities
6 Methodological Approaches to Studying Health Outcomes Associated with the Current Immunization Schedule: Options, Feasibility, Ethical Issues, and Priorities
Pages 99-126
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From page 99... ...
Therefore, the burden of disease and evidence of adequate immunogenicity when vaccines are administered together with existing recommended vaccines are established at the time of FDA approval and development of a recommendation by the ACIP. Although the committee's review of the available scientific evidence revealed that no potential adverse health outcomes that may occur after immunization with the recommended immunization schedule rose to a level of concern or biological plausibility sufficient to justify a strong recommendation for immediate study, the committee was asked to recommend methodological approaches that could be implemented should the need arise.
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From page 100... ...
The decision to initiate further studies should depend on the results of an evaluation of three considerations that the committee identified through its review of stakeholder concerns and scientific findings: 1. epidemiological evidence of potential adverse health outcomes associated with elements of the immunization schedule (such as postmarketing signals or indications of an elevated risk from ob servational or experimental studies)
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From page 101... ...
or prospective cohort studies, without the existence of supporting signals or evidence of biological plausibility. Recommendation 6-1: The committee recommends that the Depart ment of Health and Human Services incorporate study of the safety of the overall childhood immunization schedule into its processes for setting priorities for research, recognizing stakeholder concerns, and establishing the priorities on the basis of epidemiological evidence, biological plausibility, and feasibility.
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From page 102... ...
In summary, it is not possible to recommend studies with animals to inform the notion that the aggregate childhood immunization schedule results in the onset of chronic diseases. The committee also recognized the role of animal models in understanding neurological diseases, which have made important contributions to the understanding of disease processes that affect the brain in terms of structural or motor changes, such as seizures.
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From page 103... ...
Thus, the primary research questions of interest that the committee identified and that are listed below are broad and most likely too general to be readily translated into new research studies, unless biologically plausible hypotheses emerge. Among the many questions about the current immunization schedule that could be posed, the committee identified what it viewed to be the leading research questions of interest on the basis of a review of stakeholder concerns.
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From page 104... ...
4. o potentially susceptible subpopulations -- for example, children D from families with a history of allergies or autoimmune diseases -- who may experience adverse health consequences in association with immunization with the currently recommended immunization schedule exist?
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From page 105... ...
The committee recognized the vital importance of considering the population health impacts of any studies of the childhood immunization schedule. As the immunization schedule exists within a complex system consisting of individual-level protection and community immunity, studies that require any variations to the immunization schedule may have a profound impact on broader population health.
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From page 106... ...
One could argue that it would be ethical to recruit this population to an RCT comparing a group that receives the standard vaccination schedule with a group that receives no immunization. Because participants would be randomly placed in one of these study arms, at least half of the participating children, who otherwise would receive no vaccination, would receive all or part of the recommended immunization schedule.
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From page 107... ...
As the committee did not find evidence to suggest that the current schedule is unsafe, the committee concludes that any RCT comparing the current schedule with an alternative schedule that does not provide full and timely coverage of all the currently recommended vaccines would offer an unacceptable risk of vaccine-preventable diseases in individuals and in the population. The committee believes that it may be ethical to use the RCT design to evaluate the third research question, which seeks to determine how health outcomes differ for those who receive the full recommended schedule in unconventional ways.
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From page 108... ...
General Feasibility Issues As detailed in Chapter 3, RCTs to evaluate the introduction of individual vaccinations are conducted within the context of the currently recommended childhood immunization schedule. The committee found no evidence that a trial has ever been conducted to evaluate the entire immunization schedule, for example, to compare administration of the recommended schedule of vaccines with administration of an alternative schedule.
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From page 109... ...
A federal investment in an RCT of the immunization schedule would therefore be infeasible, and unless further epidemiological evidence of safety problems from observational studies reveals a safety problem, such an investment could be considered wasteful. Overall, the committee recognizes the value of the RCT in providing definitive data on the potential effects of the immunization schedule on adverse outcomes and asserts that the RCT should have a role in the overall research program on the safety of the schedule.
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From page 110... ...
Before HHS initiates further research on the entire immunization schedule, a thorough review of the biological plausibility of the association of a particular outcome with an aspect of the schedule should be conducted. Recommendation 6-2: The Department of Health and Human Services should refrain from initiating randomized controlled trials of the child hood immunization schedule that compare safety outcomes in fully vaccinated children with those in unvaccinated children or those vac cinated by use of an alternative schedule. New Observational Studies Observational studies are the cornerstone of epidemiological science and are often used to evaluate associations between exposures and outcomes in situations in which randomization to a treatment arm would be unethical or in which it would not be feasible, either because of costs or other factors, to directly assign and monitor an intervention in the study population.
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From page 111... ...
Because some Amish communities and other potential naturally occurring unimmunized populations have relatively so few unvaccinated children, the sample population of unimmunized children who could be recruited would likely be too small to provide adequate statistical power, particularly for very rare outcomes (see Appendix D)
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From page 112... ...
NCS therefore affords an opportunity to study potential health outcomes among children with a range of immunization histories, and the committee encourages such efforts through NCS and other similar cohorts to create a rich set of data for continued research. Given the opportunity available through NCS, the limits of studying distinct subgroups of naturally occurring unimmunized populations, and the high cost of pursuing prospective data collection, the committee does not consider the initiation of new prospective cohort studies to be the most feasible or fruitful approach to studying the recommended immunization schedule at this time.
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From page 113... ...
Given the comprehensive state of immunization data systems in the United States, the committee considered secondary analyses with data from existing data sets to be the most feasible option for the study of the safety of the childhood immunization schedule. In particular, a number of questions about variations in the current immunization schedule could be further investigated by the use of VSD.
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From page 114... ...
Accordingly, secondary analyses of the data in VSD databases would add to current knowledge and help answer the four primary research questions listed in Box 6-1. For example, in a review of alternative immunization schedules in the Kaiser Permanente Colorado system, VSD researchers initiated a retrospective matched cohort study to examine patterns and trends for children defined as undervaccinated at ages 2 to 24 months and compared the health care utilization rates between undervaccinated children and children vaccinated at the appropriate age.
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From page 115... ...
New approaches to the collection of additional data on a family history of allergies, autoimmune disorders, neurological disorders, and the like should be considered. These data would permit analyses of the fourth research question (about potentially susceptible subpopulations)
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From page 116... ...
This shortcoming is largely overcome in comparable systems in Scandinavia and the United Kingdom because of their universal health care systems and patient registries that contain information on medical services received from primary care providers. The use of strategies to collect health care utilization data through EHRs or provider reports after a participant has left the original health plan may warrant consideration.
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From page 117... ...
The committee noted that although VSD represents the most promising system for investigating outcomes after immunization with the recommended childhood immunization schedule, other resources discussed in Chapter 3, such as VAERS, the National Immunization Survey, and immunization information systems, are highly valued resources for monitoring vaccine safety and coverage as well. The Post-Licensure Rapid Immunization Safety Monitoring (PRISM)
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From page 118... ...
population. Secondary analyses with data from other existing databases similar to VSD would be feasible, ethical, and a lower-cost approach to investigating the research questions that the committee identified, including research on alternative immunization schedules.
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From page 119... ...
Such complications would affect both clinical trials and observational studies. Consideration of Population Impacts of Alternative Schedules Attempts to quantify the relative safety of contrasting immunization schedules need to take into account at least two separate health outcomes: (1)
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From page 120... ...
. Importantly, Swedish data also illustrate the concept of community immunity.
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From page 121... ...
is now available. Synthesis of this information together with historical incidence data to formulate validated transmission models is made possible by the use of modern inference techniques, including sequential Monte Carlo methods for hypothesis testing (Ionides et al., 2006)
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From page 122... ...
For example, the committee does not recommend a study comparing the recommended immunization schedule and no immunization at this time because a highquality randomized trial is not ethical and a prospective observational study could be complex, lengthy, and expensive and would potentially provide inconclusive results about key health outcomes after immunization. Thus, the committee proposes establishment of a process for setting priorities incorporating epidemiological and other evidence (on the basis of ormal systematic reviews)
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From page 123... ...
1997. Vaccine safety datalink project: A new tool for improving vaccine safety monitoring in the United States.
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From page 124... ...
2007. Addressing parents' concerns about childhood immunizations: A tutorial for primary care providers.
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From page 125... ...
METHODOLOGICAL APPROACHES 125 Smith, P.J., S.Y.
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