Enhancing Public Confidence in Vaccines Through Independent Oversight of Postlicensure Vaccine Safety

Abstract

The National Immunization Program of the Centers for Disease Control and Prevention is responsible for controlling infectious diseases through vaccination, but the program also plays a key role in postlicensure vaccine safety assessment. The time has come to separate postlicensure vaccine safety assessment from vaccine risk management as recommended by the National Research Council of the National Academy of Sciences.

The National Transportation Safety Board offers a useful model for developing an independent National Vaccine Safety Board that would have the authority to leverage resources and expertise of various government agencies, academia, and industry to oversee postlicensure vaccine safety investigations. Such a board would have been useful in recent vaccine safety concerns, and its independence from government programs would ensure optimal vaccine safety and enhance public confidence in vaccines.

VACCINES SAVE THOUSANDS of lives every year, but may cause side effects (e.g., mild fever, localized reactions) and rare serious adverse events (e.g., anaphylaxis, vaccine-associated paralytic polio). Vaccines are held to a higher safety standard than other biologics because vaccines are given to healthy persons and are required for school attendance.1 Most of the safety questions that arise almost every year about licensed vaccines—such as hypotheses about vaccines causing diabetes, multiple sclerosis, and other chronic diseases—prove to have little or no scientific basis. But new adverse events are discovered from postlicensure investigations such as intussusception following rhesus rotavirus vaccine2 and Guillain–Barré syndrome associated with the 1976 swine influenza vaccine.3,4 Other concerns may indicate the need for changes in products or policy even when definitive data on causal associations may be absent, for example, removal of thimerosal from vaccines administered to infants and children because of theoretical risks.5,6 The debate about the reintroduction of smallpox vaccine has heightened public awareness of safety issues because this vaccine causes more serious adverse events than other routinely administered vaccinations.7,8 The public must know that vaccine safety concerns are taken seriously and investigated by independent professionals whose primary responsibility is safety, not financial gain, public image, or program goals.

RISK ASSESSMENT VS RISK MANAGEMENT

Risk assessment is defined as “the use of the factual base to define the health effects of exposure of individuals or populations to hazardous materials and situations” and risk management as “the process of weighing policy alternatives and selecting the most appropriate regulatory action, integrating the results of risk assessment with engineering data and with social, economic, and political concerns to reach a decision.”9(p3) The National Research Council of the National Academy of Sciences recommends that federal agencies “maintain a clear conceptual distinction between assessment of risks and consideration of risk management alternatives; that is, the scientific findings and policy judgments embodied in risk assessment should be explicitly distinguished from the political, economic, and technical considerations that influence the design and choice of regulatory strategies.”9(p151) A companion report from the National Resource Council highlights the importance of including interested and affected parties so that risk characterization addresses relevant issues.10

The importance of separating risk assessment from risk management was shown in Europe after the loss of public confidence in the safety of the food supply because of bovine spongiform encephalopathy.11 A white paper issued by the European Department of Agriculture, Fisheries and Food in 2000 recognized the need to reestablish public confidence in food safety and recommended a separation of risk assessment from risk management.12 The European Union is establishing a food safety group implementing this policy.

Another example of the importance of separating risk assessment from risk management is the recently publicized $1.4 billion settlement of a conflict of interest case reached with a group of Wall Street firms. This investment scandal highlights the hazards of not having independent checks and balances in place between those who advise on the risks/merits of goods and those who may be perceived to benefit from that advice. Although these potential conflicts existed on Wall Street for a long time, it took a major stock market devaluation to bring them into question. Many firms have separated their equity research (risk assessment) and investment banking (risk management) operations in order to rebuild public trust.

Wood et al.13 have advocated the establishment of an independent, comprehensive, and systematic program of postmarketing drug surveillance. They argue that the Food and Drug Administration (FDA) lacks the resources for adequate postlicensure surveillance and FDA staff members are potentially biased as “their recommendation for approval involves substantial personal identification with that approval, and it is unlikely that those who recommend a drug for approval could later conduct a dispassionate evaluation of possible harm due to that drug.”13(p1853) To address this unmet need, Wood et al. propose a board, modeled after the National Transportation Safety Board (NTSB), with sufficient funds to mount its own ongoing studies or hold open public hearings resulting in recommendations to the FDA.

ASSESSMENT VS MANAGEMENT IN IMMUNIZATION PROGRAMS

Postlicensure surveillance for serious adverse events will always be needed because the full safety profile of a vaccine can only be determined after the vaccine has been administered to large numbers, often millions, of persons. The need for independence in postlicensure safety monitoring is stronger for vaccines than for drugs because of the large and increasing role that the federal government plays in purchasing vaccines and promoting immunization activities. The primary responsibility of the National Immunization Program is to control infectious diseases through vaccination (risk management). However, the National Immunization Program also plays an important role in postlicensure vaccine safety studies (risk assessment).

The need for separation of risk assessment from risk management in immunization programs was first pointed out after the swine flu immunization program in 1976, when a major effort was launched to vaccinate the US population against an anticipated influenza pandemic that never occurred.14 Investigations conducted by the Centers for Disease Control and Prevention (CDC) revealed that the vaccine caused Guillain-Barré syndrome, and the program was widely considered a failure because the risk of a pandemic was not reassessed after the initial decision to vaccinate was made.14,15 The CDC has provided effective epidemiological investigations of many other important vaccine safety issues, including the “Cutter incident” (in which some of the original Salk polio vaccine manufactured by Cutter Laboratories in 1955 was not fully inactivated, resulting in 260 cases of polio)4 and intussusception associated with rhesus rotavirus vaccine.16 CDC coadministers the passive Vaccine Adverse Event Reporting System with the FDA and maintains an active surveillance system that has been very valuable in assessing vaccine safety concerns.17–19 Recently, the CDC funded the Clinical Immunization Safety Assessment network that will provide additional investigations into postlicensure adverse events.20 However, the success of these activities does not guarantee that the handling of future crises will be viewed positively by the public.

The FDA has statutory responsibility for vaccine safety including licensure of vaccines and oversight of manufacturing, but ensuring public confidence in vaccines is not a primary FDA responsibility. As pointed out by Wood et al.,13 the FDA may suffer from a lack of independence and lack the resources to fully explore safety issues. Other government agencies (National Institutes of Health, Health Services Resource Administration, Department of Veterans Affairs, Department of Defense) and nongovernmental groups (pharmaceutical companies, disease advocacy organizations) have important roles in vaccine safety, but each of these groups also has primary missions or other goals that may interfere or at times conflict with its vaccine safety activities.

CURRENT VACCINE SAFETY SYSTEM

One attempt to create an independent organization to help coordinate the federal agencies involved in the national vaccine effort is the National Vaccine Program Office (NVPO).21 The NVPO is charged with achieving the highest level of prevention of human disease through immunization and the highest possible level of prevention of adverse reactions to vaccines. The NVPO director reports to the assistant secretary for health, Department of Health and Human Services. Separation of vaccine risk assessment and risk management will not be achieved by the NVPO. In 1995, Congress removed all funding for NVPO and subsequently NVPO activities from this location have been limited because of a small staff and a very limited budget. Also, the assistant secretary for health no longer has the organizational authority intended in the legislation that created the NVPO. This position has been removed from direct authority over agencies; consequently, the NVPO no longer has any real authority over the CDC or the FDA.

The CDC, FDA, and NVPO have external advisory committees to provide independent advice to these agencies. These committees include individuals who are independent of the government agencies, but the committees are limited in the scope of questions addressed. They have no authority over the agency activities, research, funding, or final decisions. Additionally, some committee members depend on these agencies and vaccine manufacturers for research funding.

The Institute of Medicine Immunization Safety Review Committee has provided some degree of independent vaccine risk assessment by conducting reviews of specific vaccine safety issues, including possible associations between measles-mumps-rubella vaccine and autism,22 hepatitis B vaccine and multiple sclerosis,23 thimerosal and learning disabilities,24 and multiple immunizations and immune dysfunction.25 However, the reviews were conducted months or years after the concerns were raised. The committee reviewed only available scientific data, as the committee does not have the authority or resources to conduct its own scientific studies or in-depth investigations.

This committee is insufficient to meet the timely needs of vaccine safety risk assessment and communication to the public at times of uncertainty. The CDC and the National Institutes of Health determine the issues addressed and could theoretically overlook important issues. Although the committee has broad expertise important for studying vaccine safety, it excludes both experts with potential financial, professional, or personal conflicts of interests with vaccine manufacturers and individuals who have served on vaccine advisory committees for the FDA, CDC, or the American Academy of Pediatrics.26 These exclusions foster impartiality, but the consequent reduction of vaccine expertise is a potential problem.

THE NATIONAL TRANSPORTATION SAFETY BOARD MODEL

Lessons learned from other government experiences suggest the need for an independent system that can conduct timely assessments of vaccine risk.27 The CDC and state and local health departments’ expertise and capacity to mobilize resources in conducting large-scale epidemiological investigations will be needed, but the oversight should be independent of the CDC and the FDA. As there are many similarities between vaccine safety and transportation safety, the NTSB is a useful model for considering the separation of risk assessment and risk management for vaccine safety. The NTSB was established in 1967, charged by Congress to investigate every civil aviation accident in the United States and significant accidents in the other modes of transportation and to issue safety recommendations aimed at preventing future accidents.28 The NTSB is responsible for maintaining the government’s database on civil aviation accidents and also conducts studies of significant transportation issues. The NTSB was initially established as an independent group, although it relied on the Department of Transportation for funding and administrative support. In 1975, the inherent conflict with the Department of Transportation was recognized and the NTSB was established as an independent agency. The NTSB makes recommendations to appropriate parties, including the Federal Aviation Administration. It does not have regulatory authority, but more than 80% of its recommendations are implemented.29

To achieve the objective of ensuring optimal safety, the NTSB is given legal authority beyond what is typically given to governmental agencies, including the ability to write subpoenas to obtain data that are needed for effective investigations. The NTSB is thus empowered to bring regulatory and industry entities together through a “party system” to examine safety issues and reduce risk where feasible. The party system is a process whereby key select players with significant expertise representing different concerns get together to facilitate the investigation. The NTSB leads the investigation but is able to leverage its own resources and utilize information (often proprietary) and expertise of affected parties. The public perceives the NTSB as highly credible and values air transportation safety. According to a recent RAND report:

The agency enjoys the reputation of being the most important independent safety investigative authority in the world; the caliber of its investigations has become the international standard. . . . The NTSB’s unique role in transportation safety is contingent on the ability of the board members and the professional staff to conduct independent investigations of accidents and major incidents, and in so doing, to assure public confidence in the safety of our national transportation system.28(pv,1–2)

NATIONAL VACCINE SAFETY BOARD

There is a need for similar independent reviews and credible public communication to ensure public confidence in vaccine safety through a National Vaccine Safety Board (NVSB). The NVSB mission to monitor postlicensure vaccine safety could be achieved by (1) funding and conducting vaccine safety investigations; (2) bringing together experts from government, industry, and academia to review all available scientific information and determine causal associations between vaccines and adverse events; (3) making recommendations to government and industry to improve vaccine safety; and (4) disseminating safety findings to the public. Achieving these goals would require persons with a broad range of expertise, including immunology, vaccines, epidemiology, biostatistics, internal medicine, pediatrics, infectious diseases, toxicology, risk assessment, risk communication, and policy.

An NVSB would have been useful for promptly addressing several recent vaccine safety issues including concerns about associations between Haemophilus influenzae type b vaccines and diabetes; measles-mumps-rubella vaccine and autism; and hepatitis B vaccine and multiple sclerosis. If an independent panel such as an NVSB had been available to point out the relatively low value of anecdotal reports and ecological data, these issues might not have created so much public concern.

An NVSB would require the authority to use a party system and independent funding to conduct and oversee safety investigations. Although an NVSB would not eliminate vaccine safety controversies or antivaccine activities, the NVSB would fulfill the expectation that the public will be informed promptly and objectively when vaccine safety issues arise and as new information becomes available. The development of an NVSB could create a vibrant system for ensuring the safest vaccine system possible and maintaining public confidence in the safety of vaccines. Our system for ensuring optimal vaccine safety and public confidence in vaccines should be strengthened now, before some real or perceived crisis results in loss of credibility due to competing priorities or conflicting interests.