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7 Conclusions and Recommendations COMMITTEE RESPONSE TO ITS STATEMENT OF TASK This final chapter highlights selected findings and conclusions and pres- ents recommendations for each section of the committee’s statement of task. The preceding chapters, especially Chapter 6, include many assessments that may be construed as the committee’s preferences among the alterna- tives presented but that fall short of formal recommendations. Vaccine safety is critically important, but a determination of safety is ultimately a value judgment. For example, some might believe that a serious adverse event that occurs once in 1 million doses is “safe enough” relative to the benefit of preventing a serious disease, whereas others may consider that risk unacceptably high. The committee did not set a specific numerical target or goal for what should be considered “safe enough.” Instead, the committee made a judgment based on the literature that failed to link ad- verse effects to schedule exposures or multiple immunizations, concluding that there is no evidence that the schedule is not safe. The committee recognized that final decisions about research studies must await knowledge of further evidence, including biological plau- sibility and/or epidemiological evidence, feasibility, cost, and the exact circumstances of stakeholder concerns, before the planning and con- duct of specific research projects. In turn, the committee believes that it would be inappropriate to make unqualified recommendations without this knowledge. The committee notes that stakeholder concerns may be used to drive a search for scientific evidence (biological or epidemiologi- cal), although such concerns would not be sufficient motivation to embark 127

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128 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY on costly clinical research, such as new randomized controlled trials or cohort studies. The committee thus decided to make five general recommendations. Three recommendations focus on improvements to understanding stake- holder concerns, harmonizing research methods, and sequencing the process for selecting research questions. Two recommendations focus on research methods, including randomized controlled trials and data systems that would enable ongoing and improved observational studies. Statement of Task (Part I): Review scientific findings and stakeholder concerns related to the safety of the recommended childhood immuni- zation schedule. Summary of Stakeholder Concerns The committee’s findings and conclusions about stakeholder concerns are presented in Chapter 4. Although the committee identified the con- cerns of some parents about the number, frequency, and timing of immu- nizations in the overall immunization schedule, the committee did not find in its literature review that clinicians, public health personnel, or policy m ­ akers have similar safety concerns. Among the latter groups, the child- hood immunization schedule is considered to be among the most effective and safe of the public interventions available to prevent serious disease and death. However, although health care professionals have much information about individual vaccines, they have much less information about the effects of administration of multiple vaccines at a single visit or the timing of the immunizations. Additionally, the cited concerns of health care professionals include efficacy of certain vaccines as well as appropriate delivery and com- munication regarding the recommended childhood immunization schedule. Although the 2010 National Vaccine Plan addresses the need to provide health care providers with more timely, accurate, and transparent informa- tion about the benefits and risks of vaccines, the plan does not specifically address strategies to assist providers with questions about the safety of the immunization schedule (HHS, 2010). The committee concluded that par- ents and health care professionals would benefit from more comprehensive and detailed information with which to address parental concerns about the safety of the immunization schedule. Such information should clearly address vaccine-preventable diseases, the risks and benefits of immuniza- tions, and the safety of the immunization schedule. The committee’s literature review highlighted the lack of high-quality evidence supporting stakeholder concerns (the priority stakeholders are listed in Box 4-1) about the immunization schedule. In its role to ensure

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CONCLUSIONS AND RECOMMENDATIONS 129 vaccine safety, the federal government has already prioritized the engage- ment of stakeholders in multiple activities, as detailed in the 2010 National Vaccine Plan and implementation efforts, as well as the Centers for Dis- ease Control and Prevention’s Immunization Safety Office scientific agenda (CDC, 2011; HHS, 2010). However, an effective national vaccine program will require more complete information on stakeholder concerns about the safety of the immunization schedule, the severity of vaccine-preventable diseases, individual- and population-level immunization rates, vaccine ef- ficacy, and the delivery and supply of vaccines recommended in the child- hood immunization schedule. Improved communication between public health authorities and parents requires improvements to the clarity of the information provided, as well as the building of trust and the use of a sys- tematic approach to elicit public concerns. Further research into the type of questions that parents seek to answer by the use of the scientific methods of social, behavioral, and decision science is indicated. On the basis of the committee’s literature review and public testimony, the committee strongly endorses the need for research to understand the public’s knowledge, beliefs, and concerns about vaccines and vaccine-pre- ventable diseases in particular, which is a key strategy in the 2010 National Vaccine Plan (HHS, 2010). It must be acknowledged that the methods used in most immunization studies do not permit a detailed analysis of the impact of parental concerns on the decision to immunize their children. Al- though the committee found that the largest safety concerns exist among a subset of parents, the concerns of multiple stakeholders should be included as part of the efforts of the National Vaccine Program Office (NVPO). For example, health care providers have much knowledge about individual vaccines but less information about the effects of administering multiple vaccines at a single visit or the timing of the immunizations. Recommendation 4-1: The committee recommends that the National Vaccine Program Office systematically collect and assess evidence re- garding public confidence in and concerns about the entire childhood immunization schedule, with the goal to improve communication with health care professionals, and between health care professionals and the public regarding the safety of the schedule. Summary of Scientific Findings The committee’s findings and conclusions about the safety of the immu- nization schedule on the basis of the information in the scientific literature are presented in Chapter 5. The committee encountered two major issues. First, the concept of the immunization “schedule” is not well developed in the scientific literature. Most vaccine research focuses on the health out- comes associated with single immunizations or combinations of vaccines

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130 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY administered at a single visit. Even though each new vaccine is evaluated in the context of the overall immunization schedule that existed at the time of review, individual elements of the schedule are not evaluated once it is adjusted to accommodate a new vaccine. Key elements of the immunization schedule—for example, the number, frequency, timing, order, and age at the time of administration of vaccines—have not been systematically examined in research studies. The second major issue that the committee encountered during the re- view of the scientific literature was uncertainty over whether the scientific literature has addressed all health outcomes and safety concerns. The com- mittee could not determine whether its list of health outcomes was complete or whether a more comprehensive system of surveillance might identify other outcomes of potential safety significance. In addition, the conditions of concern to some stakeholders, such as immunological, neurological, and developmental problems, are illnesses and conditions for which the etiology, in general, is not well understood. Further research on these conditions may clarify their etiologies. Finally, the committee found that evidence from assessments of health outcomes in potentially susceptible subpopulations of children who may have an increased risk of adverse reactions to vaccines (such as children with a family history of autoimmune disease or allergies or children born prematurely) was limited and is characterized by uncertainty about the defi- nition of populations of interest and definitions of exposures and outcomes. Most children who experience an adverse reaction to immunization have a preexisting susceptibility. Some predispositions may be detectable prior to vaccination; others, at least with current technology and practice, are not (IOM, 2012, p. 82). In summary, to consider whether and how to study the safety and health outcomes of the entire childhood immunization schedule, the field needs valid and accepted metrics of the entire immunization schedule (the “exposure”) and clearer definitions of health outcomes linked to stake- holder concerns (the “outcomes”) in rigorous research that will ensure validity and generalizability. Recommendation 5-1: To improve the utility of studies of the entire childhood immunization schedule, the committee recommends that the National Vaccine Program Office develop a framework that clarifies and standardizes definitions of • key elements of the schedule, • relevant health outcomes, and • populations that are potentially susceptible to adverse events.

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CONCLUSIONS AND RECOMMENDATIONS 131 Statement of Task (Part II): Identify potential research approaches, methodologies, and study designs that could inform this question, in- cluding an assessment of the potential strengths and limitations of each approach, methodology, and design, as well as the financial and ethical feasibility of doing them. Summary of Methodological Issues The committee’s findings and conclusions about research approaches are presented in Chapter 6. The committee parsed the phrase “this ques- tion” in Part 2 of the statement of task into four broad research questions in Box 7-1. The committee then discussed general research approaches with the potential to answer these questions: ongoing research with data from exist- ing data systems, research with enhanced data from existing data systems, prospective observational studies, and randomized controlled trials. The committee also recognized that to advance the knowledge about the safety BOX 7-1 Leading Research Questions of Interest to Select Stakeholders 1.  ow do child health outcomes compare between those who re- H ceive no vaccinations and those who receive the full currently recommended immunization schedule? 2.  ow do child health outcomes compare between (a) those who H receive the full currently recommended immunization schedule and (b) those who omit specific vaccines? 3.  children who receive the currently recommended immunization For schedule, do short- or long-term health outcomes differ for those who receive fewer immunizations per visit (e.g., when immuniza- tions are spread out over multiple occasions), or for those who receive their immunizations at later ages but still within the recom- mended ranges? 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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132 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY of the immunization schedule, certain enhancements to the research infra- structure will be needed, as detailed in Chapter 6. The committee recognizes that the establishment of priorities for re- search will be a challenge. Thus, the committee proposes a process for setting priorities that recognizes stakeholder concerns and establishes these priorities on the basis of epidemiological and other evidence (based on for- mal systematic reviews), biological plausibility, and feasibility. Before the U.S. Department of Health and Human Services (HHS) initiates further research on the entire immunization schedule through its agencies—most notably CDC, FDA, the National Institutes of Health, and NVPO—the biological plausibility of the association of a particular outcome with an aspect of the immunization schedule must be thoroughly reviewed. Along these lines, previous IOM vaccine safety committees have assessed the mechanisms by which vaccines potentially cause adverse events by identifying and evaluating the clinical and biological evidence (from hu- man, animal, and in vitro studies) for individual vaccines. Furthermore, the recent IOM Committee to Review Adverse Effects of Vaccines developed categories for a mechanistic assessment of the weight of the evidence. Each assessment considers clinical information from case reports and clinical and experimental evidence from other sources (IOM, 2012). 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. The decision to initiate further studies should be based on 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 as- sociated with elements of the immunization schedule (such as post- marketing signals or indications of elevated risk from observational studies); 2. biological plausibility supporting hypotheses linking specific as- pects of the immunization schedule with particular adverse health outcomes; and 3. concern about the immunization schedule’s safety expressed by stakeholders, which should initiate efforts to explore the two previ- ous considerations.

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CONCLUSIONS AND RECOMMENDATIONS 133 The committee acknowledges the evidence that reducing vaccine cover- age is associated with increases in vaccine-preventable disease and found only inconsistent and anecdotal evidence to imply that the recommended immunization schedule is not safe. Furthermore, existing systems for the de- tection of adverse events provide confidence that the existing childhood im- munization schedule is safe, and the committee recognizes that the federal government invests considerable resources to ensure vaccine safety. Never- theless, some stakeholders have suggested that further work is warranted, such as a comparison of vaccinated children with unvaccinated children or children receiving immunizations on alternative immunization schedules. The committee supports the National Vaccine Advisory Committee Safety Working Group statement that “the strongest study design, a pro- spective, randomized clinical trial that includes a study arm receiving no vaccine or vaccine not given according to the current recommended sched- ule, would be unethical and therefore cannot be done” (NVAC, 2009, p. 38). In Chapter 6, the committee presents the formidable ethical and feasibility problems associated with the conduct of randomized controlled trials of children who receive all recommended immunizations and children who receive none of them and randomized controlled trials of children who receive all recommended immunizations and children who receive the recommended immunization on an alternative schedule. There are very low observed rates of adverse events with vaccination, which is another factor sffecting feasibility of a randomized controlled trial. Because of these problems, the committee concludes that a randomized controlled trial com- paring the recommended schedule with any alternative schedule would be unethical and infeasible and could increase the risk of vaccine-preventable diseases in individuals and in the community. Furthermore, the committee found that a trial of a modified version of the ACIP schedule—one that would disperse the timing of vaccinations so that children are visiting health care professionals more often but receiving fewer shots at each visit—would be ethical; however, it would add substan- tial costs to both parents and providers and, moreover, may be unaccept- able to insurers if its effectiveness—measured as a decreased rate of adverse safety outcomes—was negligible. This modified schedule would provide immunizations within the time intervals approved by ACIP and would ad- dress the concern about immunization with too many vaccines at one office visit, but the committee did not view this option to be feasible for study. In light of the ethical and feasibility requirements and the available evidence, the committee concludes that new randomized controlled trials of the childhood immunization schedule are not justified at this time. Recommendation 6-2: The Department of Health and Human Services should refrain from initiating randomized controlled trials of the child-

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134 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY 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.  The committee also reviewed opportunities to study groups that choose not to vaccinate their children by use of a prospective cohort study design. However, such a study would not conclusively reveal differences in health outcomes between unimmunized and fully immunized children for two main reasons. First, the sample populations often suggested for study (such as some religious populations) may be too small to adequately power such a comparative analysis, particularly for very rare adverse health outcomes. Such a study would also need to account for the many confounding vari- ables that separate these naturally occurring unimmunized populations from the average U.S. child, including lifestyle factors and genetic variables. The committee finds that secondary analyses of existing systems are more promising approaches to examination of the research questions that the committee identified in future studies of the childhood immunization schedule. The Vaccine Safety Datalink (VSD) is a useful collaborative proj- ect that could conduct both postmarketing surveillance and longer-term targeted research. The ability to augment routinely collected administra- tive data in VSD with data from parent interviews and reviews of medical records for a selected study population is an important strength. VSD is currently the best available system for studying the safety of the immunization schedule in the United States. VSD should strive to improve the generalizability of its data to the U.S. population as a whole by enhanc- ing the quality of its demographic information and by expanding its scope to include more diversity in its study populations. Secondary analyses with data from other existing databases (that might be modeled on VSD) could be a feasible, ethical, and cost-effective means of investigating several re- search questions that the committee identified. The committee recognizes that the commitment to VSD studies by the managed care organizations currently receiving funding through VSD needs to be sustained to continue to build on existing efforts. The committee concludes that VSD is a valuable component of the federal research infrastructure and will be the best-suited source of data for studying the childhood immunization schedule. Its utility will be expanded with the addition of more detailed demographic data and family medical histories. Recommendation 6-3: The committee recommends that the Depart- ment of Health and Human Services (HHS) and its partners continue to fund and support the Vaccine Safety Datalink project to study the safety of the recommended immunization schedule. Furthermore, HHS should

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CONCLUSIONS AND RECOMMENDATIONS 135 consider expanding the collaboration with new health plan members and enhancing the data to improve its utility and generalizability. CONCLUDING OBSERVATIONS The committee’s efforts to identify priorities for recommended research studies did not reveal a base of evidence suggesting that the childhood immunization schedule is linked to autoimmune diseases, asthma, hyper­ sensitivity, seizures or epilepsy, child developmental disorders, learning disorders or developmental disorders, or attention deficit or disruptive behavior disorders. While the committee found that there is no scientific evidence to justify the majority of safety concerns, perceptions dictate pa- rental support and actions. Therefore further study of the full immunization schedule as well as further study to understand stakeholder perceptions and how they are formed may help improve awareness and education efforts. Stakeholder concerns should be one of the elements used to drive searches for scientific evidence, but these concerns alone, absent epidemiological or biological evidence, do not warrant the initiation of new high-cost random- ized controlled trials. The committee concludes that data from existing data systems may be used to conduct observational studies and offer the best means for ongoing research efforts of the immunization schedule’s safety. The committee found no significant evidence to imply that the recom- mended immunization schedule is not safe. Furthermore, existing surveil- lance and response systems have identified adverse events known to be associated with vaccination. The federal immunization research infrastruc- ture is strong. A key component is the VSD project, which with ongoing support will be able to feasibly address the committee’s identified key research questions. Although the committee concludes that protection of children from vaccine-preventable diseases is of higher importance than testing of alternative immunization schedules without epidemiological or biological evidence indicating a safety problem, VSD should continue to examine the health outcomes of people who choose alternative schedules. Looking to the future, the committee supports the work of the federal research infrastructure in ensuring that stakeholders are involved in all stages of development, implementation, evaluation, and dissemination of the immunization schedule. As electronic medical records become more commonly used, they may provide an opportunity to capture complete im- munization data linked with hospital discharge records that will be useful to future studies. Further, the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program may have the capability to monitor rare ad- verse events potentially associated with the childhood immunization sched- ule. Initiatives such as the National Children’s Study also hold promise; it

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136 THE CHILDHOOD IMMUNIZATION SCHEDULE AND SAFETY will be one of the most comprehensive research efforts focused on studying children’s health and development. The childhood immunization schedule may become more complex over time as scientific advances are made and new vaccines are developed. Feasible research approaches to study potential adverse health outcomes will emerge only with a sustained and substantial federal commitment to research on vaccine safety. REFERENCES CDC (Centers for Disease Control and Prevention). 2011. Immunization Safety Office scien- tific agenda. Atlanta, GA: Immunization Safety Office, Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention. HHS (Department of Health and Human Services). 2010. 2010 National Vaccine Plan. Wash- ington, DC: Department of Health and Human Services. IOM (Institute of Medicine). 2012. Adverse effects of vaccines: Evidence and causality. Wash- ington, DC: The National Academies Press. NVAC (National Vaccine Advisory Committee). 2009. Recommendations on the Centers for Disease Control and Prevention Immunization Safety Office draft 5-year scientific agenda. Washington, DC: National Vaccine Advisory Committee.