2
The Safety of Vaccines and Vaccination Practices

The starting point for the contemporary vaccine safety system was the National Childhood Vaccine Injury Act (NCVIA) of 1986.1 Enacted in the face of mounting public concern over both the safety of certain licensed childhood vaccines and the economic viability of the vaccine industry (Mariner, 1992), the act had two principal objectives. The first objective was to ensure that even as the public’s health is protected through immunization, a system exists to compensate the small number of individuals who suffer injury thought to be caused by vaccines without the delays and costs associated with tort litigation. Simple fairness requires a mechanism to compensate those thought to be injured by vaccines that are properly manufactured and administered, that are recommended for universal use, and in some cases required by states for school entry to protect public health.2 The other principal objective of the law was to create a climate of safety through adoption or expansion of optimal public health and clinical practices (e.g., monitoring vaccine safety, provision of printed patient information3) and the application of the best science to vaccine safety.

The fact that the founding of the National Vaccine Program (and by extension its executive entity, the National Vaccine Program Office [NVPO]) was among the desired outcomes in an act focused on vaccine safety is not

1

Public Law 99-660, codified at 42 U.S.C. 201; see Appendix C.

2

All states allow medical exemptions from school-entry vaccination requirements, 48 states allow religious exemptions from vaccination, and 19 states allow philosophical exemptions as well (NCSL, 2009).

3

The law specifically requires the provision of Vaccine Information Statements.



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2 The Safety of Vaccines and Vaccination Practices The starting point for the contemporary vaccine safety system was the National Childhood Vaccine Injury Act (NCVIA) of 1986.1 Enacted in the face of mounting public concern over both the safety of certain licensed childhood vaccines and the economic viability of the vaccine industry (Mariner, 1992), the act had two principal objectives. The first objective was to ensure that even as the public’s health is protected through immu- nization, a system exists to compensate the small number of individuals who suffer injury thought to be caused by vaccines without the delays and costs associated with tort litigation. Simple fairness requires a mechanism to compensate those thought to be injured by vaccines that are properly manu- factured and administered, that are recommended for universal use, and in some cases required by states for school entry to protect public health.2 The other principal objective of the law was to create a climate of safety through adoption or expansion of optimal public health and clinical practices (e.g., monitoring vaccine safety, provision of printed patient information3) and the application of the best science to vaccine safety. The fact that the founding of the National Vaccine Program (and by extension its executive entity, the National Vaccine Program Office [NVPO]) was among the desired outcomes in an act focused on vaccine safety is not 1 Public Law 99-660, codified at 42 U.S.C. 201; see Appendix C. 2 All states allow medical exemptions from school-entry vaccination requirements, 48 states allow religious exemptions from vaccination, and 19 states allow philosophical exemptions as well (NCSL, 2009). 3 The law specifically requires the provision of Vaccine Information Statements. 

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN coincidental. The act lists the program’s nine responsibilities4 with regard to intra-governmental coordination and coordination with stakeholders; most refer to the safety of vaccines and to adverse events. NVPO’s coordinating role was and remains an essential part of the vaccine safety system estab- lished by the act. This chapter examines how the plan could enhance the vac- cine safety system; a more extensive discussion of the coordination required to implement the National Vaccine Plan is provided in Chapter 6. The first part of this chapter provides an overview of four major com- ponents of the 1986 legislation and their current status: (1) vaccine safety surveillance and research; (2) information and communication about vac- cine safety (discussed in Chapter 3); (3) the program of compensation for injuries thought to be caused by vaccine; and (4) the National Vaccine Program and Plan. The second part of the chapter is organized around four recommendations about priority actions for vaccine safety in the National Vaccine Plan. In the history of vaccine development and regulation, concern has focused on both vaccine efficacy (and correlates of clinical protection) and vaccine safety. Both vaccine efficacy and vaccine safety are relative: no vac- cine is 100 percent effective or 100 percent safe. The use of vaccination has reduced the incidence of disease (and therefore the immediate threat to any individual) and, concomitantly, the burden of fear of disease-related morbidity, disability, and death. The lower risk of disease has understand- ably led to higher expectations of vaccine safety. The story of polio vaccine illustrates the evolving nature of a vaccine’s risk-benefit balance and of the understanding of that balance as additional information on possible adverse events accrues and as disease incidence changes. In the 1950s when poliomyelitis was endemic in the United States, the benefit of live, attenu- ated poliovirus vaccine for the individual and the community was judged to greatly outweigh the risk of vaccine-associated paralysis, which occurred at a rate of about 1 case per 2.4 million doses distributed (CDC, 2009b). By 2000, when polio had been eliminated from the Western Hemisphere, this risk of vaccine-associated paralytic polio was judged no longer acceptable in the United States. An enhanced inactivated polio vaccine (IPV), first licensed by the Food and Drug Administration (FDA) in 1987, was ultimately recom- mended by the Advisory Committee on Immunization Practices (ACIP) in 2000 for exclusive use in routine immunization (CDC, 2000; Moylett and Hanson, 2004). 4 The nine responsibilities include vaccine research, vaccine development, “safety and ef- ficacy testing of vaccines,” “licensing of vaccine manufacturers and vaccines,” “production and procurement of vaccines,” “distribution and use of vaccines,” “evaluating the need for and the effectiveness and adverse effects of vaccines and immunization activities,” “coordinating governmental and non-governmental activities,” and funding federal agencies in implementing the National Vaccine Plan.

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 THE SAFETY OF VACCINES AND VACCINATION PRACTICES Interventions given to healthy persons to prevent disease are required to have a low risk-to-benefit ratio when compared to therapeutic interventions. Many childhood vaccines that are recommended for universal use by ACIP are required by states for attendance in licensed day care facilities and public schools, and thus administered to large segments of the population (e.g., nearly the entire annual birth cohort of more than 4 million children). Some adult vaccines are also universally recommended, others are recommended for specific occupations (e.g., health care workers) and, in some cases, required by employers. A substantial proportion of the adult population receives influenza vaccine each year (for example, between two-thirds and three-quarters of adults 65 years of age or older received influenza vaccina- tion in 2008; CDC, 2006). The process of anticipating, detecting, and quantifying the risks of rare adverse events following immunization presents an enormous chal- lenge. Vaccine studies submitted as part of Biological License Applications to FDA’s Center for Biologics Evaluation and Research (CBER) have his- torically included several thousand individuals. Rare but serious adverse events may follow vaccination, sometimes at rates in the range of one in a million vaccine recipients. Even vaccine trials including 100,000 or more participants may not have adequate statistical power to detect such rare adverse events. Delaying licensure after efficacy has been shown in order to amass additional evidence related to rare adverse events associated with a candidate vaccine would result in continuing cases and deaths due to the preventable disease. After FDA licensure, as knowledge about a vaccine’s safety increases when large numbers of individuals are immunized, additional safety assess- ment becomes possible, complementing pre-licensure data. Vaccine safety researchers both at FDA and outside government have emphasized the equal importance of adequate pre-licensure study and post-licensure surveillance for “signals” of adverse events. It is challenging to detect a true “signal” of a vaccine safety problem amidst the considerable “noise” of coincidental, only temporally related events. Licensure of second generation rotavirus vaccines offers a clear example in which pre-licensure studies put a special emphasis on vaccine safety because of knowledge about the risk of intussusception acquired after introduction of the first licensed rotavirus vaccine. The large studies un- dertaken for the second-generation rotavirus vaccines—70,000 subjects for RV5 (bovine-based, RotatTeq) and nearly 75,000 for RV1 (human-based, Rotarix)—reflect a specific safety concern related to the first rotavirus vac- cine (Ellenberg et al., 2005; GSK, 2008; Heyse et al., 2008). The FDA Amendments Act of 2007 has strengthened CBER’s author- ity to require post-licensing studies. FDA may require the manufacturer to conduct post-licensure studies of vaccine safety that meet certain specifica-

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN tions (e.g., design, size). FDA monitors a wide range of safety data from the systems described below. The Centers for Disease Control and Prevention (CDC), in addition to joint management of the Vaccine Adverse Events Reporting System (VAERS), implements rapid epidemiologic evaluation of possible safety signals, such as the evaluation of intussusception following the use of RRV-TV (rhesus-based, RotaShield). A CASE STUDY OF VACCINE SAFETY SYSTEM FUNCTIONING The federal vaccine safety system’s response to evaluate reported ad- verse events following immunization with RRV-TV entailed an extensive effort. The response spanned at least 19 states, involved 40 of CDC’s Epi- demic Intelligence Service officers, and drew on the capabilities of federal, state, and local public health agencies and health care organizations to locate and verify vaccination histories and outcomes in infants given the rotavirus vaccine and to undertake scientific analysis.5 A timeline of events culminating in the withdrawal of the ACIP recommendation for rotavirus vaccine is provided in Table 2-1. The experience with RRV-TV illustrates comprehensively the safety system’s components, their capabilities, and their functioning. Subsequent efforts to develop, license, and monitor the safety of RRV5 and RV1 were informed by lessons learned from the first vaccine and led to changes in study design and regulatory expectations for rotavirus vaccines (e.g., a re- quirement for an unprecedented expansion of the size of the Phase III clinical trials; targeted post-licensure surveillance). At the time it licensed RV1 in 2008, FDA required a large post-licensure observational safety study in the United States to assess the potential seri- ous risk of intussusception and other serious adverse effects (specifically Kawasaki disease, hospitalizations due to acute lower respiratory tract infections, and convulsions) in vaccine recipients. Requirements included a study sample size of 44,000 vaccinated subjects (to be adjusted based on the background rate of intussusception), and a study design “to detect an increased relative risk of intussusception due to vaccine with a relative risk of 2.5 or greater and with 80 percent power” (FDA, 2008a). The study began June 2009 and is expected to end in 2012. 5 Personal communication, D. Snider, M. Wharton, T. Murphy, U. Parashar, CDC, August 25-26, 2009.

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55 THE SAFETY OF VACCINES AND VACCINATION PRACTICES TABLE 2-1  Rotashield  Vaccine  Timeline  (1999-2001) Date Event Before licensure  In the absence of rotavirus vaccines, there are 3 million cases  of rotavirus infection per year (in children under age 5); for  500,000 cases, medical attention is sought, and 60,000 to  70,000 are hospitalized. According to Rennels (2000), rotavirus gastroenteritis caused 25  pediatric deaths per year. There is no known association between wild rotavirus infection  and intussusception. The rotavirus vaccine manufacturer sponsors 27 clinical trials  in 9 countries involving more than 10,054 children who  received the vaccine (Rennels, 2000). Study data are submitted to FDA as part of the Biological  License Application process. ACIP forms a rotavirus working group, and the group’s review of  serious adverse events in the pre-licensure trials finds 5 cases  of intussusception in children who received the vaccine and 1  case among 4,633 children receiving placebo (Rennels, 2000;  Rennels et al., 1998). Rotavirus vaccinea (RRV-TV) is licensed by FDA for use in  August 31, 1998 infants (CDC, 1999). Vaccine package insert includes reference to intussusception  as potential adverse event (Rennels, 2000). However,  background rates of intussusception are not statistically  different from those identified during pre-licensure study  (Rennels et al., 1998; see below).  Intussusception in the following groups Rate (%) Study placebo recipients  0.022 Study vaccine recipients (all doses)  0.05 Study vaccine recipients   (dose proposed for licensure)  0.024 Health plan population 1995-1996 (California Kaiser Permanente study)  0.074 General population 1991-1995 (New York State)  0.05 FDA requires Phase IV (post-licensure study) of adverse events  (CDC, 2004). Intussusception search code is added to VAERS database  (Rennels, 2000). continued

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN TABLE 2-1 Continued Date Event October 1998 Study comparing vaccinated children to unvaccinated children shows no statistically significant difference in intussusception rates between the two groups and “failed to demonstrate an etiologic association between natural or vaccine rotavirus infection and intussusception” (Rennels et al., 1998). December 1998 FDA-required Phase IV (post-licensure) study by Northern California Kaiser Permanente begins. December 1998 The first report of intussusception following rotavirus vaccine to VAERS (over the first months of 1999, 1-4 reports of intussusception are received by VAERS) (Zanardi et al., 2001). March 19, 1999 ACIP recommends use of rotavirus vaccine as a 3-dose series at 2, 4, and 6 months of age (CDC, 1999). June 2, 1999 Reports of intussusception submitted to VAERS reach 10; most cases occur within 1 week of the first dose of vaccine— “temporal clustering after receipt of RRV-TV suggested a causal relationship” (CDC, 1999). Preliminary findings from the Phase IV study in managed care organizations give additional cause for concern, although “these data did not have adequate power to establish a statistically significant difference in incidence of intussusception among vaccinated and unvaccinated children” (HHS, 2008a). June 17, 1999 CDC alerts ACIP about emerging epidemiologic information (CDC, 2004). CDC initiates two epidemiologic studies: a 19-state case control study and a population-based retrospective cohort study (Chang et al., 2002; Kramarz et al., 2001; Murphy et al., 2001). CDC investigators review medical records of all VAERS reports of intussusception following rotavirus vaccine (Zanardi et al., 2001). July 6, 1999 Number of cases of intussusception following rotavirus vaccination reaches 15 (CDC, 2004). July 16, 1999 CDC recommends that providers suspend use of the rotavirus vaccine (CDC, 2004). The announcement is followed by an increase in reports to VAERS (HHS, 2008a). October 22, 1999 ACIP withdraws its recommendation for use of rotavirus vaccine at ages 2, 4, and 6 months (CDC, 1999). December 31, 1999 Number of cases of intussusception following rotavirus vaccination reaches 112 (Verstraeten et al., 2001). 2000-2001 Verstraeten et al. (2001) conduct a capture-recapture analysis of intussusception after rotavirus vaccine between December 1, 1998, and June 30, 1999, and find that VAERS reporting was 47% complete. a Tetravalent Rhesus-based Rotavirus [RRV-TV] RotaShield.

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 THE SAFETY OF VACCINES AND VACCINATION PRACTICES PART I: COMPONENTS OF THE 1986 LEGISLATION Reporting and Investigating Adverse Events: Assessing Causality Post-licensure vaccine safety surveillance is an important component of the vaccine safety system that begins operation for a given vaccine at the time it is licensed by FDA and health care providers begin to administer it. Surveillance for adverse events following immunization—based on reporting by the public, health care providers and manufacturers—is conducted by two entities: VAERS and the Vaccine Safety Datalink (VSD). The military also provides vaccination to its personnel, and the Department of Defense operates its own military immunization program and the Vaccine Health- care Centers Network (2009) that provide “expert consultative services for vaccine adverse events case management and reporting; research in vaccine safety and quality assurance; and healthcare provider/patient education and training programs.” Before the 1986 NCVIA was enacted, reports of adverse events follow- ing immunization were captured through two different systems. One was a system administered by FDA and intended to gather spontaneous vaccine adverse event reports from manufacturers, pharmacists, health care provid- ers, and the military. The other system, the Monitoring System for Adverse Events Following Immunization established in 1978, was administered by CDC and intended to collect reports from parents whose children received publicly purchased vaccine. As a result of the law, the two reporting systems were integrated into VAERS, which began operating in November 1990 and currently receives approximately 30,000 reports annually from manu- facturers, health care providers, and vaccine recipients or their parents or guardians (CDC, 1990; HHS, 2008b). Approximately 85 percent of reports received by VAERS describe mild events, while 15 percent describe serious adverse events (life-threatening, requiring hospitalization, or resulting in death) (CDC, 2009a). (See Figure 2-1 for an overview of the federal vaccine safety system.) The VAERS system has strengths and weaknesses. A major strength is that anyone may submit a vaccine adverse event report to VAERS including consumers. Weaknesses of VAERS include incomplete reporting of adverse events, varying quality and completeness of individual reports, and several important biases (Iskander et al., 2006; Varricchio et al., 2004). Although the system is capable of capturing rare and unusual adverse events following immunization, and CDC staff use sophisticated data mining techniques to maximize the usefulness of VAERS data to detect safety signals (Iskander et al., 2006), reports to VAERS may simply indicate a perceived relationship to the vaccine, usually based on a coincidental temporal association between vaccine administration and the adverse event. To assess causality, one needs to compare the expected rate of the reported condition in a comparison

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN NIH role (and a Pre-licensure Post-licensure (Phase I, II, III) (Phase IV) small FDA role) FDA Licensure studies studies in vaccine R&D CISA VAERS VSD (collaboration (collaboration (collaboration with between CDC and between CDC, AHIP, CDC, AHIP, MCOs ) FDA) & research centers) Causality Assessment Vaccine Injury Risk Compensation Communication Program FIGURE 2-1 In December 2008, HHS and NVPO released a detailed overview of the federal vaccine safety system in some detail, with some reference to non- government stakeholders (HHS, 2008). In addition to the federal agencies charged with various components of researching, regulating, monitoring, and communicating about vaccine safety, many other stakeholders, including vaccine manufacturers, academic researchers, healthFigure 2-1, editable R01625, care providers, public health agencies, and the public make important contributions. NOTE: The thick dotted line represents the point at which vaccines enter the market, become recommended for use, and become increasingly used in the population. Risk communication is discussed in more detail in Chapter 3 of the present report. Adapted from HHS (2008a). For the sake of simplicity, does not reflect Department of Veterans Affairs (VA) and Department of Defense (DoD) contributions to the federal vaccine safety system (see discussion in text). Acronyms: CISA: Clinical Immunization Safety Assessment; MCOs: Managed Care Organizations; NIH: National Institutes of Health. group. Because there are no comparison groups available for VAERS, data the system collects are almost always only one part of the information needed to assess whether or not there is an association between a vaccine and an adverse event. Due to incomplete reporting and lack of appropriate comparison groups, neither the incidence of an adverse event nor the relative risk of the event in vaccinated individuals can be calculated (Varricchio et al., 2004). Thus, VAERS data cannot ordinarily establish that an epidemio-

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 THE SAFETY OF VACCINES AND VACCINATION PRACTICES logic, much less, a causal, association exists between the suspected adverse event and immunization. The VSD program represents a model for government-academia- health care delivery system collaboration involving CDC, FDA, AHIP, and university-based researchers. VSD utilizes databases from eight managed care organizations that provide medical care for 8.8 million children and adults. Because VSD has the capability of generating appropriate compari- son groups it can also analyze data that establish an epidemiologic associa- tion that can provide stronger evidence for causality than that provided by case reports. VSD conducts active surveillance for adverse events of interest and for any adverse event resulting in a health care contact within a time period of interest following vaccination (i.e., VSD data can be searched systematically for specific events or time periods). After the introduction of new vaccines, VSD investigators develop hypotheses, often on the basis of reports to VAERS or data from pre-licensure trials, and the VSD database facilitates their investigation. In the past several years, VSD has developed a new capability—rapid cycle analysis of its database, that enables VSD researchers to conduct near real-time (weekly) active surveillance of vac- cine safety. One of VSD’s strengths is the link to electronic medical records and access to medical charts for clinical information and vaccination histories. Limitations of the VSD include its sample size, which, though large, may not be adequate to detect association for extremely rare adverse events, for example those that occur in one in a million individuals. VSD is currently conducting monitoring of adverse events for the following vaccines: menin- gococcal conjugate vaccine, Tdap, MMRV, seasonal influenza, quadrivalent HPV, combination DTaP-Hepatitis B-IPV, and RRV5. VSD is also preparing for active surveillance using Rapid Cycle Analysis for the vaccine against novel influenza A (H1N1), RRV1, DTaP-IPV, and DTaP/IPV/Hib vaccines. Another component of the vaccine safety system is the Clinical Im- munization Safety Assessment (CISA) network that is a collaborative effort between CDC, AHIP, five academic medical institutions, and one managed care organization. CISA investigators conduct intensive clinical study of cases of adverse events following immunization, in an effort to better under- stand the complex relationship to vaccines and inform the development of guidance for clinicians on the management of serious adverse events (Halsey et al., 2009). Some of CISA’s work leads to publication (Slade, 2009). One of CISA’s collaborators is the Department of Defense’s network of Vaccine Healthcare Centers (VHC). CISA’s role and expertise are comple- mentary to those of VSD. While VSD takes an epidemiologic approach to assessing causality, CISA’s approach is focused on understanding the patho- genesis of adverse events following immunization at the individual level, as the only component of the vaccine safety system that conducts clinical and

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0 PRIORITIES FOR THE NATIONAL VACCINE PLAN basic science research and that provides consultation (via phone and e-mail) to providers managing adverse events following immunization (Halsey et al., 2009; Slade, 2009). FDA’s role in monitoring vaccine safety (together with its effectiveness, as they cannot be considered in isolation from one another [IOM, 2007]) spans a vaccine’s entire lifespan. The regulatory role begins when a vaccine developer approaches the agency to discuss preliminary plans for a Biologic License Application and request an Investigational New Drug protocol to allow clinical trials with humans. That role continues during regulatory review, through the point of licensure, which today includes requirements for post-licensure surveillance (i.e., Phase IV) studies, and for as long as the vaccine is manufactured or used. As noted earlier, FDA collaborates with CDC in managing the VAERS system and in overseeing post-licensure safety research. The processes by which the pre-licensure review of a vaccine fully anticipates and informs the post-licensure phase have undergone some strengthening in response to the FDA Amendments Act. For example, FDA has gained authority to require post-licensure studies and specific plans to minimize and manage risks posed by medical products including vaccines. FDA is in the early stages of establishing the Sentinel Initiative, a system for large-scale surveillance of medical product safety, including vaccines. The initiative is intended “to link and analyze healthcare data from mul- tiple sources” by accessing (and analyzing) data from 25 million patients by July 1, 2010, and from 100 million patients by July 1, 2012 (FDA, 2008b). FDA is supporting researchers to evaluate various methodologic approaches and other dimensions of the use of very large databases to evaluate medi- cal product safety. A national discussion among both federal partners and non-government stakeholders about vaccine safety research priorities could also inform investigations based on the sentinel system. This will require greater coordination between CDC, FDA, and other federal agencies, and the committee hopes, strong coordination with national health informa- tion technology efforts. The committee noted that the plans of the Office of the National Coordinator for Health Information Technology (ONCHIT) include objectives on linkage with immunization registries and recognition of immunization status as an important component of electronic health records. Some ONC documents, such as the “Meaningful Use Matrix” (in- tended to guide the meaningful use of electronic health records to engage patients, provide real-time access to all medical information, and support quality and safety as well as improved access and the elimination of health care disparities [ONCHIT, 2009]) also include references to FDA’s Sentinel Initiative. Although there are considerable barriers to the successful develop- ment and implementation of health information technology, the committee hopes that what it has noted is an indication that health information tech- nology planning at the highest levels of government is coordinated with the

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 THE SAFETY OF VACCINES AND VACCINATION PRACTICES national medical product safety surveillance effort. At the time of this writ- ing, CDC, FDA, and VSD have developed and are implementing a system to monitor the safety of the H1N1 pandemic influenza vaccine. The network for Post-Licensure Rapid Immunization Safety Monitoring (PRISM) has been established to link immunization registries in a number of states with the databases of large health maintenance organizations. This system con- siderably expands VSD’s sample size and could perhaps provide some idea of how the Sentinel Initiative may function (HHS et al., 2009). Finally, in addition to its role in VAERS, VSD, and CISA, CDC also is the nation’s lead public health agency, able to respond rapidly to the emergence of a vaccine safety question with the expertise needed to assess urgent public health issues such as disease outbreaks or serious vaccine safety concerns. CDC is able to deploy epidemiologists and other experts to conduct case-control interviews, conduct laboratory research, work with state public health personnel and health care providers, and carry out other activities needed to intensively investigate a potential serious adverse event following immunization. The experience with the first rotavirus vaccine, RRV-TV, described above, is an example of the federal and state public health capabilities in quickly responding to and elucidating the meaning of a vaccine safety “signal” captured through VAERS or by other means (e.g., ac- tive surveillance through VSD). After a vaccine’s licensure, CDC’s efforts to ascertain vaccine safety (and effectiveness) complement those carried out by FDA, in addition to activities conducted jointly, such as VAERS and VSD. Information and Communication The social context of vaccine safety has changed in the decades since the 1986 act was signed into law. As immunization has resulted in vastly lower rates of some diseases and entirely eliminated other diseases, the direct relationship between vaccine and disease prevention has become less and less visible to the public. Today diseases such as polio, diphtheria, and congenital rubella syndrome no longer top the list of fears parents have for their children’s health; polio has been eradicated from the Western Hemi- sphere, and other diseases may be mere memories or only rare occurrences. A major decrease in the rate of a vaccine-preventable disease may alter the risk-benefit analysis for a vaccine targeting that disease. Other changes in the past two decades include social and cultural transformations that have shaped public attitudes toward vaccination both positively and negatively. These include the emergence of active and engaged patients, and the rapid availability of vast amounts of information via the Internet, and the emer- gence of organized groups opposed to immunization. The committee be- lieves that one major challenge in communicating about vaccines relates to their dual identity as a medical intervention to protect an individual against

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN The scientific criteria of such a framework for prioritization might in- clude, but are not limited to: (a) Assessment of the nature and extent of existing evidence for a pos- sible association of an adverse event with a vaccine. (b) Determination of the individual or public health burden of potential adverse events following immunization. (c) Consideration of the feasibility of scientifically rigorous study of a safety concern. (d) Assessment of biological plausibility of a causal association between an adverse event and a vaccine. Coordination and Vaccine Safety One of the five dimensions of the vaccine safety system outlined by the 1986 act refers to the overarching National Vaccine Program, and by ex- tension, to its operating arm, NVPO. The HHS Comprehensie Reiew of Federal Vaccine Safety Programs and Public Health Actiities (2008a) states that NVPO coordinates HHS vaccine safety activities and explains that NVAC provides a forum for the exploration of vaccine safety policy issues that arise among HHS agencies (see Box 2-1). Although the legislation was clearly intended to address the need for intra-departmental coordination of Box 2-1 Role of the National Vaccine Program Described in the 1986 Act “[C]oordinate and provide direction for research carried out in or through the National Institutes of Health, the Centers for Disease Control, the Office of Biolog- ics Research and Review of the Food and Drug Administration, the Department of Defense, and the Agency for International Development on means to induce human immunity against naturally occurring infectious diseases and to prevent adverse reactions to vaccines.”a a And to “coordinate and provide direction for activities carried out in or through the National Institutes of Health, the Office of Biologics Research and of the Food and Drug Administration, the Department of Defense, and the Agency for International Development to develop the techniques needed to produce safe and effective vaccines”; and “coordinate and provide direction for safety and efficacy testing of vaccines carried out in or through the National Institutes of Health, the Centers for Disease Control, the Office of Biologics Research and Review of the Food and Drug Administration, the Department of Defense, and the Agency for International Development.”

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 THE SAFETY OF VACCINES AND VACCINATION PRACTICES vaccine safety activities, meaningful, effective coordination to address gaps in the science vaccine safety, as one example, has not been achieved. This may, at least in part, be due to the factors (lack of funding, human resources, authority, and visibility) that have prevented NVPO from functioning as intended by the 1986 law. Additional discussion of NVPO and interagency coordination is provided in Chapter 6. Multiple government agencies and private sector entities handle aspects of vaccine safety, therefore, developing and implementing a national-level safety research agenda requires coordination among federal agencies, such as NIH and FDA, and with stakeholders (such as health care providers who work with special populations, and vaccine manufacturers) to as- sume joint responsibility for and work collaboratively on some of the great challenges in vaccine safety research. The committee found evidence that the system can work well to address safety concerns. However, achieving coordination among government agencies, understanding and addressing the public perception of the safety system’s competence and transparency, and allocating resources for vaccine safety research that are commensu- rate with the expanding task (i.e., surveillance and study of the safety of a growing number of licensed vaccines currently in use) all remain major challenges. Factors that may have slowed the pace of progress in vaccine safety include the absence of broader NIH participation in vaccine safety research; NVPO’s lack of authority and resources needed to fully perform the coordinating role (with respect to vaccine safety issues, among others) called for by legislation; and the lengthy process over the past several years of finding a permanent home in CDC for ISO, and until recently, lack of stable, permanent ISO leadership. The absence of interagency coordination on vaccine safety was rec- ognized in a 1998 Task Force on Safer Childhood Vaccines report that recommended that the Interagency Vaccine Group (IAVG) formed in the 1980s take on as a primary responsibility the coordination of vaccine safety activities, and that NVPO function as the secretariat for the IAVG in that area (see Box 2-2). The current IOM committee was struck by the Task Force report’s continuing relevance more than a decade later. The committee recognized that the task force was seeking to fill a major gap in the coordina- tion necessary to ensure an effective vaccine safety program. The task force discussed the Interagency Vaccine Group, an internal government entity that is still in operation, and described a potential role for it in strengthening co- ordination of vaccine safety activities, from communication, to monitoring and surveillance, to safety research. The Task Force report also stated that “[o]verall coordination of programs involving both broad vaccine issues and vaccine safety is the responsibility of the Vaccine Interagency Group [sic]

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0 PRIORITIES FOR THE NATIONAL VACCINE PLAN Box 2-2 An Example of Coordination Within HHS: Role of the Interagency Vaccine Group The 1998 Task Force on Safer Childhood Vaccines defined IAVG’s role as follows: A) The IAVG would monitor the vaccine safety activities of the various agen- cies and work to improve interagency communication. It would also facilitate and monitor progress on the investigation and evaluation of reports of serious or frequent adverse events. i) Evaluate data relevant to vaccine safety, which may currently be scat- tered among various agencies and manufacturers. ii) Ensure periodic reviews of the safety of licensed vaccines and their recommended immunization schedules. If appropriate, propose studies to address areas where additional data may be informative or supportive, such as in special target groups or programs. iii) Ensure effective communication among existing advisory committees that focus on vaccines and immunization, including specifically the Advisory Com- mission on Childhood Vaccines, the Advisory Committee on Immunization Prac- tices, the National Vaccine Advisory Committee, and the Vaccines and Related Biological Products Advisory Committee. B) The IAVG would be expected to seek routine technical consultation from an expert external advisory body. The Task Force is committed to the concept that the public health is best served by the continued pursuit of safer and more effective vaccines and by the safe use of existing vaccines through improvements in the immunization schedule and delivery of vaccines. The recommendations presented in this report are congruent with the Nation’s immunization and vaccine goals presented in the U.S. National Vaccine Plan in 1994.a a The task force report added: “Vaccine safety oversight resides among a broad group of advisory committees and government groups. Most notable are the DHHS immunization- related advisory committees including the Advisory Commission on Childhood Vaccines, the Immunization Practices Advisory Committee, the Microbiology and Infectious Diseases Review Advisory Committee (MIDRAC) of NIAID, the National Vaccine Advisory Committee (NVAC), and the Vaccines and Related Biological Products Advisory Committee. The Department of Defense (DoD) is advised on vaccine and other issues by the Armed Forces Epidemiologi- cal Board (AFEB). Overall coordination of programs involving both broad vaccine issues and vaccine safety is the responsibility of the Vaccine Interagency Group of the National Vaccine Program Office. Although safety is not the main or only focus of these groups, aspects of vac- cine safety coordination and oversight exist within all of them” (p. 276).

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 THE SAFETY OF VACCINES AND VACCINATION PRACTICES of the National Vaccine Program Office” (NIAID, 1998).10 More recently, the NVAC State of the Program 2008 report, stated that “[f]ederal efforts have suffered from a lack of coordination and oversight of vaccine-related activities, highlighted most recently by the need for the Secretary of HHS to empanel a special interagency vaccine safety working group to better address this growing concern” (NVAC, 2009a). NVAC’s observation raises two related but distinct points about federal vaccine safety activities. Despite some potential overlap, coordination and oversight are somewhat different functions, with different rationales, and likely different solutions. Coordination refers to working together effec- tively to define priorities, to achieve a shared vision and to resolve strategic issues that exceed one agency or stakeholder’s capabilities. Operationally, coordination may mean working to avoid wasteful duplication of effort and inefficient use of funds. Oversight is defined as “watchful care” and typically refers to the function of assuring accountability and propriety. In the realm of vaccine safety, there is a history of dialogue about independent oversight of vaccine safety monitoring and research as a response to concern about a perceived inherent conflict of interest in government in general and CDC specifically, given its responsibility both for preventing disease through the optimal use of vaccines and for monitoring post-licensure vaccine safety in the population (CDC, 2005; Cooper et al., 2008; Salmon et al., 2004). The committee recognizes the desire to strengthen confidence in the safety system, and is aware of some of the arguments employed. The topic of the placement of an entity conducting vaccine risk management as op- posed to risk assessment was discussed at the committee’s April 2009 stake- holder meeting. The committee deems only the matter of intragovernmental coordination (HHS, its agencies, and DoD) as directly germane to its task and to the preparation and implementation of the National Vaccine Plan (the primary instrument for effecting coordination in the National Vac- cine Program). The matter of independent oversight falls outside this IOM committee’s scope of work. The IAVG’s functioning in the area of vaccine safety does not necessarily match the description in the 1998 task force report, and there is no reason why it should. The committee believes that the job description developed by the task force remains relevant, that it calls for a different type of entity (in addition to IAVG in its ongoing role), and that such a role would ideally be performed in a setting that permits meetings that are open to the public. 10 The IAVG has continued to operate, and the committee has found several references to it in NVAC minutes between 2004 and 2009 (for example, a reference to the group’s role in shaping the charge to the former IOM Immunization Safety Review Committee, a reference to a 2008 meeting with the ISO on its draft agenda, and a reference to its role in developing the National Vaccine Plan).

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN This IOM committee believes that a federal advisory group has the potential to play a crucial role both as a facilitator of coordination (especially with stakeholders, and as a supporter of NVPO’s role in coordinating within government), and also as a somewhat independent source of guidance on vaccine safety issues. NVPO provides staff support and works very closely with NVAC, the advisory committee established to advise the Secretary of HHS on matters related to National Vaccine Program. The role played by the NVAC Vaccine Safety Working Group in reviewing policy matters related to vaccine safety appears to have contributed an independent and credible perspective on vaccine safety. With NVPO support, the group also has engaged the public in thoughtful dialogue about challenging matters of vaccine safety policy. While a working group structure provides useful flex- ibility, its activities may be less transparent than those of a subcommittee, as subcommittees are required to follow the Federal Advisory Committee Act. Recommendation 2-3: The National Vaccine Plan should include the establishment and scope of work of a permanent NVAC vaccine safety subcommittee to: (a) provide guidance on the activities described in Recommen- dations 2-1 and 2-2 in a public and transparent manner; (b) provide guidance about the identification and evaluation of potential safety signals; and (c) publish on a biennial basis a review of potential safety hypotheses; current vaccine safety activities including those of pre- and post-licensure studies, VAERS, VSD, and CISA; and planned priorities for research. The NVAC subcommittee could be informed of potential safety signals and the actions planned to investigate the signal and related public com- munication. Public representation on the subcommittee is crucial, and the committee notes that NVAC has set strong precedent in including public or consumer representatives (all of its recent committee and working group rosters attest to this; refer to Appendix E for a short history of HHS public engagement activities related to vaccines). Funding for Vaccine Safety Research A major theme in the stakeholder comments about Goal 2 of the draft National Vaccine Plan was the inadequacy of funding for vaccine safety research (IOM, 2009). This concern has been voiced elsewhere by other commentators in the field (for example, Cooper et al., 2008). The commit- tee believes that there are two major areas where vaccine safety research

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 THE SAFETY OF VACCINES AND VACCINATION PRACTICES TABLE 2-2 Comparison of Immunization Safety Office and Vaccines for Children Program Funding Year ISO Funding Vaccines for Children Program Funding 2004 $21.8 million >$1 billion 2005 $22.8 million $1.2 billion 2006 $21.7 million $1.7 billion 2007 $21.5 million $1.9 billion 2008 $21.7 million ~$3 billion SOURCES: Personal communication, C. Johnson, CDC, July 7, 2009; Shefer, 2008. warrants additional support. First, the CDC Immunization Safety Office needs more funding and staff to conduct its work. The second area pertains to NIH research and would necessitate a partial reorientation of some of the agency’s research priorities to ensure a greater balance between classic investigator-initiated research, which is a crucial engine of vaccine innova- tion, and research prompted by public health concerns specifically focused on vaccine safety, including some level of directed research, and not simply limited to very basic or early clinical research. There are strong obstacles to such a reorientation in NIAID (the NIH institute with primary responsibilities for vaccines), especially in the absence of a strong coordinating entity within the National Vaccine Program that can help align program-wide needs (such as vaccine safety research) with solutions. The committee reviewed the lengthy list of NIH-funded vaccine- related research projects and found that a small proportion appear to have some relevance to safety, and an even smaller subset have safety as a primary objective. As a simple illustration, a search of the database of NIH-funded vaccine-related research yielded 24 studies (out of 3,003) that referred to safety in the title (6 from NIAID, 18 funded by other institutes), and the vast majority appear to be pre-licensure Phase I or II studies. This paucity of research on vaccine safety is congruent with stakeholder comments at the committee’s April 2009 meeting, where the low level of NIH funding for vaccine safety research was a major theme. The IOM committee con- tacted NIAID to inquire about the status of the Program Announcement for Research to Advance Vaccine Safety (first introduced in 2008), what and how many proposals had come in, and what proposals were funded. The institute’s response was to refer the committee to the RePORTER database to search for the two relevant funding codes.11 The committee did so in August 2009 but found no information about funded research pertaining to the two program announcements. 11 Personal communication, K. Callahan, NIH, July 20, 2009.

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 PRIORITIES FOR THE NATIONAL VACCINE PLAN Funding for vaccine safety research conducted and supported by CDC is also limited. Although the childhood and adolescent immunization schedule has grown between 2004 and 2008 (with the addition of two rotavirus vac- cines and two vaccines against human papilloma virus, and new combina- tion vaccines, among others), the budget for CDC’s Immunization Safety Office has not. Table 2-2 is provided to illustrate that while funding of vaccine purchases for the Vaccines for Children entitlement program (that may be a reasonable proxy for government expenditures on vaccines) has increased three-fold between 2004 and 2008, the ISO budget has remained unchanged. Funding for vaccine safety monitoring and research has not grown commensurate with the widening task (e.g., a growing list of rec- ommended vaccines) and parallel investment in the vaccine supply. Thus, despite the fact that the universe of potential vaccine safety questions and signals can be expected to expand with the addition of new vaccines, the funds available to support, for example, VSD’s Rapid Cycle Analysis and CISA’s in-depth clinical studies of vaccine adverse event pathogenesis, have not increased to match the growing responsibilities of ISO. The committee believes that the current climate of support for science- based policy and for reforming health care offers opportunities not only to enhance coordination and increase the visibility of vaccine safety activities, findings, and policy decisions, but also to strengthen the funding allocated to the crucial tasks of monitoring and studying the safety of licensed vaccines. Stakeholders such as academia, industry, and the public could contribute to the vaccine safety system and are important to include in dialogue about the national vaccine safety research agenda discussed above and in devis- ing innovative mechanisms to fund important research that currently does not have well-established funding mechanisms to address it. With regard to academia and its contributions to the safety research agenda, stakeholder comments identified a need to comprehensively integrate education about vaccines and immunization in professional education, and also to train the next generation of vaccine safety researchers in relevant disciplines. Recommendation 2-4: The National Vaccine Plan should incor- porate concrete steps to expand and strengthen vaccine safety research, including: • enhanced funding for CDC’s Immunization Safety Office activities, including support of extramural research; • enhanced funding for FDA’s safety monitoring activities; and • expansion of NIH vaccine safety activities to include re- search portfolios, funding through requests for proposals, program announcements, and creation of a study section dedicated to vac- cine safety research.

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 THE SAFETY OF VACCINES AND VACCINATION PRACTICES Funding could be allocated to each federal agency to support activi- ties that implement the identified priorities as appropriate to each agency’s research capabilities and strengths. CONCLUDING OBSERVATIONS A dearth of vaccine safety research initiatives to address public concern about vaccine safety will not strengthen public confidence in the immuniza- tion system. In the legal arena for example, absence of an adequate body of good scientific evidence and a mere preponderance of the scant, often flawed evidence available may result in compensation of off-table injuries that may not be causally related to vaccines, adding to public uncertainty about the safety of vaccines. As mentioned earlier in this chapter, most discussions about the safety of vaccines raise questions about communication, and one of the important topics in vaccine communication is vaccine safety. The links between Goals 2 and 3 in the National Vaccine Plan were also very evident at the committee’s information-gathering meetings with national stakeholders. Communica- tion, or “informed vaccine decision making,” as the topic is framed in the draft plan, is discussed in detail in Chapter 3. It is important to recognize that given the current social and cultural climate, many discussions about vaccine safety will have a strong undercurrent of references to public con- fidence in the system. REFERENCES CDC (Centers for Disease Control and Prevention). 1990. Current trends vaccine adverse event reporting system—United States. MMWR 39(41):730-733. CDC. 1999. ACIP Rotairus Vaccine Recommendation. Available: http://www.cdc.gov/mmwr/ Preview/Mmwrhtml/00056669.htm [accessed September, 2009]. CDC. 2000. Poliomyelitis prevention in the United States: Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 49(RR05):1-22. CDC. 2004. Suspension of rotavirus vaccine after reports of intussusception—United States, 1999. MMWR 53(34):786-789. CDC. 2005. Blue Ribbon Panel Meeting, Summary Report, June  and , 00. Available: http://www.cdc.gov/od/ads/brpr/brprsumm.htm [accessed January 27, 2009]. CDC. 2006. Influenza and pneumococcal vaccination coverage among persons aged >65 years—United States, 2004–2005. MMWR 55(39):1065-1068. CDC. 2009a. Frequently Asked Questions about VAERS. Available: http://vaers.hhs.gov/vaers. htm [accessed August 13, 2009]. CDC. 2009b. Poliomyelitis. Available: http://www.cdc.gov/vaccines/pubs/pinkbook/downloads/ polio.pdf [accessed August 2009]. Chang, E.J., K.M. Zangwill, H. Lee, and J.I. Ward. 2002. Lack of association between rotavi- rus infection and intussusception: Implications for use of attenuated rotavirus vaccines. Pediatr Infect Dis J 21(2):97-102. Cooper, L.Z., H.J. Larson, and S.L. Katz. 2008. Protecting public trust in immunization. Pediatrics 122(1):149-153.

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