infrastructure, in the absence of data to suggest that the current schedule is unsafe, the committee must reject on ethical grounds any RCT design that compares the current schedule with an alternative that does not involve full vaccination within the permitted time windows. The committee believes that if clearly defined, biologically plausible hypotheses emerge from observational studies—either studies based on current resources, such as VSD, or studies with newly recruited cohorts—then these could serve as the basis for further research by the use of studies with the RCT design. 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 childhood immunization schedule that compare safety outcomes in fully vaccinated children with those in unvaccinated children or those vaccinated 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. Observational studies can involve either primary data, in which new data are obtained by the investigators to examine study hypotheses, or secondary data analysis, in which instances investigators analyze data that have been previously collected. In its consideration of the use of observational methods to address the four research questions of interest to stakeholders concerned about the safety of the immunization schedule identified in Box 6-1, the committee discussed potential options and challenges for studies with both primary data (in this section), and secondary data (in the section that follows).

Prospective Cohort Studies

Prospective cohort studies, which monitor—forward in time— populations selected on the basis of their exposure status, would be the most ambitious options involving primary data collection to address research questions, such as comparison of the health outcomes between children who receive no vaccinations and those who receive the full, currently recommended immunization schedule. As was mentioned earlier in



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