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© 2004 American Public Health Association
COMMENTARY |
Roger Bernier is with the National Immunization Program, Centers for Disease Control and Prevention, Atlanta, Ga. Karen Midthun is with the Center for Biologics Evaluation and Research, Food and Drug Administration, Washington, DC.
Correspondence: Requests for reprints should be sent to Roger Bernier, PhD, MPH, 1600 Clifton Rd, Mailstop E-05, Atlanta, GA 30333 (e-mail: rbernier{at}cdc.gov).
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ABSTRACT |
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Because of the potential for conflicts of interest, Salmon et al. propose in this issue the creation of an independent vaccine safety board to assume responsibility for assessing the safety of licensed vaccines.
We believe that the current system at the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) facilitates needed interactions between those involved in risk assessment and risk management, provides substantial safeguards against conflicts of interest, and results in sound decisions.
The CDC, given its role in promoting immunization, may be perceived to have a greater potential conflict and plans to review its vaccine safety activities. Both agencies recognize the importance of transparency in considering vaccine safety and welcome the opportunity to work with the public and the medical community to improve the quality of scientific information and decisionmaking.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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THE ARTICLE BY SALMON et al.1 in this issue of the Journal proposing a new national vaccine safety board provides us the opportunity to more fully describe the current postlicensure vaccine safety monitoring system in the United States and to comment on the authors’ proposal from our perspective as scientists working within the agencies mentioned in their article. As acknowledged by Salmon and his colleagues, the current US system for assessing the safety of vaccines postlicensure has been very effective, and US licensed vaccines have an excellent safety record. When potential problems do arise, recognition and response have been rapid. This capability was illustrated recently by the rapid identification of a potential safety problem by the Food and Drug Administration (FDA) and the Centers for Disease Control and Prevention (CDC) and the subsequent removal of rotavirus vaccine from the routine childhood immunization schedule only months after its introduction in 1999, when proactive postlicensure monitoring that had been put in place at the time of the vaccine’s approval led to the discovery of a risk for intussusception.
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CURRENT SYSTEM |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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At present, postlicensure monitoring of the safety of vaccines in the public sector is shared principally by the FDA’s Center for Biologics Evaluation and Research and the CDC’s National Immunization Program (NIP). This monitoring function is carried out through a variety of activities, including postlicensure studies targeted to specific safety issues, surveillance of and response to adverse events reported after vaccination, and active surveillance and research designed to answer outstanding questions or new questions that arise. An example is research involving the use of the Vaccine Safety Datalink, a consortium of managed care organizations with automated immunization and health records on millions of US children.
In addition, NIP and the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health have sponsored an independent Institute of Medicine assessment and review of concerns or hypotheses about vaccine safety topics, and NIAID independently sponsors extramural research, which contributes to a better understanding of vaccine safety. Other federal agencies, such as the Department of Defense, contribute and share important and relevant information about vaccine safety in military populations, and the Health Resources and Services Administration (HRSA) addresses injuries potentially caused by vaccines through its National Vaccine Compensation Program.
Also, the FDA, the CDC, and the HRSA receive ongoing vaccine-related advice from 3 independent committees, the FDA’s Vaccines and Related Biological Products Advisory Committee, the CDC’s Advisory Committee on Immunization Practices, and the Advisory Commission on Childhood Vaccines, respectively. A fourth independent committee, the National Vaccine Advisory Committee, works with the National Vaccine Program Office of the Department of Health and Human Services to provide direct advice to the assistant secretary for health on crosscutting vaccine issues. The individuals who serve on these advisory committees include consumer representatives as well as physicians and scientists who are external to the federal government and have expertise in different subject matter areas; all committee members are screened in regard to conflicts of interest.
Ultimately, the vaccine safety monitoring system in the US public sector is a collaborative network of multiple public entities that provide many complementary and overlapping mechanisms to ensure the overall safety of vaccines. No single entity predominates and all work together, providing multiple checks and balances.
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THE PROBLEM ACCORDING TO SALMON ET AL. |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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Salmon et al. have proposed a change in the current system because both the FDA and the CDC may have competing responsibilities related to vaccines, and these competing responsibilities may be in conflict. The FDA has the legal and regulatory responsibility to assess the safety and efficacy of investigational vaccines and determine whether they should be licensed, and, after licensure, it has the responsibility to continue to assess known and potential new risks from these vaccines, which might potentially require a recall or some other change in use. Given its regulatory responsibilities, the FDA has stringent controls in place to prevent financial conflicts of interest with the industry that it regulates or, when necessary, to manage such conflicts (e.g., recusing an individual from certain activities when conflicts cannot be eliminated). These safeguards have helped allow the FDA to provide independent, science-based regulatory oversight.
One could argue that a potential conflict, although not of a financial nature, might arise because the FDA might be reluctant to declare a vaccine unsafe that it had previously declared safe. To help bolster this process within the FDA, the group that has the lead responsibility for monitoring safety postlicensure is housed in a different office from the group with lead responsibility for prelicensure safety and efficacy assessments. The FDA’s responsibility to ensure vaccine safety extends throughout the lifetime of the product, and close collaboration between these groups in the prelicensure and postlicensure phases is critical to this function. The seamless nature of the FDA’s activities in both of these phases is essential in considering decisions not only after licensure but also beforehand about licensure itself, including the need for and design of postlicensure study commitments and ongoing surveillance. This continuity and close collaboration are essential in responding to new information and concerns in a timely, informed manner.
The CDC has the responsibility to make policy recommendations about the best public health use of vaccines once licensed and to assess any possible new risks discovered postlicensure that might require a change in these policies regarding use. NIP has the capacity to rapidly assess and respond to new information about the safety of vaccines and to issue new recommendations that can be implemented within days. For example, in 2003 new information about adverse cardiac events following smallpox vaccination was assessed and new recommendations issued within days of the first reports becoming available. A potential conflict of interest could be perceived at the CDC, where the public health mission of the program includes responsibility for control and prevention of infectious diseases through promoting vaccination, as well as a responsibility to monitor the safety of vaccine use in disease prevention and control. At the FDA, the responsibility is fundamentally one of risk assessment and management and does not include promotion of licensed products.
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THE PROPOSAL OF SALMON ET AL. |
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As alluded to earlier, Salmon et al. call for separation of postlicensure vaccine safety assessment and risk management at the FDA and the CDC. The reason is not that there is any evidence that potential conflicts of interest have actually resulted in biased or mistaken decisions about vaccine safety. Rather, Salmon et al. believe that "the time has come to separate postlicensure vaccine safety assessment from vaccine risk management as recommended by the National Research Council (NRC) of the National Academy of Sciences (NAS)."1(p947)
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MISREADING THE NRC |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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In our view, Salmon et al. appear to have misunderstood the position taken by the NRC in its 1983 report Risk Assessment in the Federal Government: Managing the Process.2 This red-covered report is often referred to as the "mis-red book" because it is seen as having advocated a strict separation between risk assessment and risk management functions. While it is correct to state that the NRC recommended that a clear conceptual distinction be maintained between risk assessment and risk management, Salmon et al. fail to point out that the emphasis of the recommendations is really on the term "conceptual."
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THE NRC POSITION IN 1983 |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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In fact, the NRC made the following statement in 1983:
Each regulatory agency should commit itself to safeguarding the distinction between the processes of risk assessment and risk management. One among several suggestions for accomplishing this safeguarding is to restructure the formal organization, separating an agency’s or program’s risk assessment staff from its policymaking staff, possibly by establishing a separate risk assessment unit outside the agency. However, the Committee does not recommend that agencies use any particular organizational arrangement for risk assessment. One might surmise that separating the staffs would help to reduce the likelihood that risk management considerations will influence risk assessment, but our survey of agency structures provided no clear evidence that such an influence was related to the degree of administrative separation.2(p152)
The report continues: "Formal separation has disadvantages that must be balanced against its value in maintaining a distinction between risk assessment and risk management. Risk assessment and risk management functions are analytically distinct, but in practice they do—and must—interact."2(p152) Finally: "Because drawbacks are likely to be most pronounced in the case of extra-agency separation, the Committee does not believe that it is appropriate to remove the risk assessment function and place it in an organization completely separated from the regulatory agencies."2(p153)
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THE NRC POSITION IN 1996 |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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Over the past 20 years, the NRC appears to have further strengthened its view regarding the importance of ensuring an interaction between the risk assessment and risk management functions. In its 1996 report Understanding Risk: Informing Decisions in a Democratic Society, the NRC states that
the traditional view of the risk decision process makes a sharp distinction between 2 functions, risk assessment (understanding) and risk management (action). . . . The conceptual distinction . . . remains useful for various important purposes, such as insulating scientific activity from political pressure and maintaining the analytic distinction between the magnitude of a risk and the cost of coping with it. For the purpose of improving decision-relevant understanding of risk and making that understanding more widely accepted, however, a rigid distinction of this sort does not provide the most helpful conceptual framework. The reason, in brief, is that the analytical activities generally considered to constitute risk assessment are not sufficient by themselves to provide the needed understanding. 3(p33–34)
Thus, good risk assessment needs to integrate the perspectives of and input from risk managers just as good risk management needs to integrate analyses from risk assessments. It is not our purpose in this short article to address the specific strengths or weaknesses of the proposal of Salmon and his colleagues. However, we cannot fail to point out as the NRC has, that formal separation of risk assessment and risk management has its disadvantages. Any fundamental changes in the current system, such as those proposed by Salmon et al., would be of unproven efficacy, redundant, and costly. The additional resources that would likely be needed, if available, could be more beneficial if directly used to improve vaccine safety, such as by implementing active, automated real time surveillance systems for adverse events or conducting focused research on vaccine quality and safety.
Also, adding a new organizational structure could cause "disconnects" and delays when actions are needed or could limit the range of options considered for intervention; in any case, it would inevitably present its own set of other shortcomings, some of which may not be foreseeable and would have unintended consequences. In our view, the real issue at present is not that of changing the current system in a fundamental way, since that system is working well, as Salmon et al. acknowledge. Rather, the issue is whether an already well-functioning system that has multiple safeguards and successfully integrates risk assessment and risk management as recommended by the NRC might be still further improved. On that point, several ideas could be put forth and discussed, such as those offered by the NRC.
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THE NRC FRAMEWORK FOR THE RISK DECISION PROCESS |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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The latest NRC framework3 for an optimal risk decision process consists of "an analyticdeliberative process" in which the objectives are to (1) get the science right, and (2) get the right science, (3) get the right participation, (4) get the participation right, and (5) develop an accurate, balanced, and informative synthesis. We agree with the objectives of the NRC in terms of decisionmaking about risks and, in particular, decisionmaking about vaccine safety risks. We believe that these objectives are best accomplished when the process is an iterative one involving both those doing the science and those using the science, a process wherein significant conflicts of interest are prevented and there are robust opportunities for input from the public and outside experts.
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BENEFITS OF THE CURRENT SYSTEM |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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The current structures at the FDA and the CDC, in which risk assessment and management interact under 1 organizational umbrella, facilitate communication between decisionmakers and the scientists with diverse expertise (including expertise in clinical medicine, epidemiology, statistics, and basic science) who are doing the assessments. In turn, this facilitated communication makes it possible for scientists to take account of the viewpoints of decisionmakers in formulating the ways in which problems are defined for analysis. Likewise, ease of communication makes it possible for decisionmakers to better understand than they otherwise would the strengths and weaknesses of the available evidence, the assumptions that have been made in any given analysis, and the degree of uncertainty attached to the final information provided. In the end, all participants can be (and can feel) adequately informed within the limits of available knowledge.
Also, under the current arrangements, the CDC and the FDA are able to more easily maintain first-rate scientific capability to conduct research studies and investigations and know how to interpret and use the data in developing policy options and strategies. As noted by the NRC, "even if risk assessment were performed outside the agency, a scientific staff representing many different disciplines would still be required, to ensure that an assessment would be interpreted and used correctly."2(p140)
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POTENTIAL CONFLICTS OF INTEREST |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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We acknowledge the need to protect against both perceived and real conflicts of interest. In the current era, there have been highly publicized and distressing examples of conflicting responsibilities in the business and financial communities leading to questionable conduct or decisions. The public’s trust in both governmental and nongovernmental institutions has sometimes been strained, and the public health community must remain mindful of the overall public climate in which it operates as it seeks to sustain use of existing vaccines and introduce new vaccines. In an era where most vaccinepreventable diseases are no longer common in the United States, it is understandable that safety concerns, even unproven ones, have become increasingly prominent. Clearly, continued effort to earn and maintain the public trust is a critical component of public service in these times and an important component of maintaining the high vaccination rates needed to protect America’s children and at-risk adults.
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WHAT MORE COULD BE DONE? |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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Several safeguards to ensure that high standards are met for the science conducted at the CDC and the FDA are in place, in the current US system overall and at the FDA in particular, and have been extremely effective in regard to keeping vaccines safe; however, more safeguards and improvements may be needed to maintain public trust at the highest levels. For example, the risk decision process, as pointed out by the NRC, includes both scientific elements and participation elements. To date, the US system has emphasized more the participation of scientists and decisionmakers in risk assessment and risk management and relatively less the participation of citizens and stakeholders.
The FDA and the CDC secure significant public participation through measures such as consumer representation on advisory committees and open public meetings with time set aside for public comment. As suggested by the NRC, additional and more deliberative public participatory activities can be considered to better inform vaccine decisionmaking and enhance public trust.
For example, NIP has undertaken extensive public consultations in connection with decisionmaking about the design and conduct of a thimerosal follow-up study of children in the Vaccine Safety Datalink. Similarly, the FDA recently provided extensive opportunities for public input into proposals for new policies updating its regulatory processes; these policies will enhance risk management and postmarket pharmacovigilance activities and increase their integration with premarket risk assessment. Provision of access to government data, which would permit reanalyses of existing studies (as has been done in the case of the Vaccine Safety Datalink since 2002), and provision of more opportunities for investigatorinitiated research of new vaccine safety questions are additional mechanisms that can help to provide information and sustain public trust in the reliability of overall vaccine risk assessments.
Even in the setting of such recent activities, any large, multifaceted program such as the US vaccine safety program deserves to be reviewed periodically, because there is always room for improvement. For this reason, the CDC, which could be perceived as having a greater potential conflict of interest because of its roles in advocating vaccination and in obtaining reduced prices for the public sector by purchasing large quantities of vaccines on behalf of state health departments, plans to undertake an agency review of its vaccine safety activities with the goal of identifying any desirable changes. This review will examine any additional safeguards that could be introduced in regard to how the vaccine safety program is structured and operated, including an updated appraisal of the issues raised by Salmon et al. The FDA will continue to work closely with the CDC on all vaccine safety matters.
The FDA also will continue to encourage the increased development of needed scientific data on vaccine safety as well as provide increased opportunities for broad public and scientific input into important vaccine safety investigations and deliberations. Both the FDA and the CDC welcome the ongoing opportunity to work with the public and with the medical and public health communities to build on and improve the quality of the scientific information and informed decisionmaking that have been successful in helping to ensure that US licensed vaccines are as safe as possible, with the goal of sustaining the great advances that have been made against vaccine-preventable diseases.
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Acknowledgments |
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We thank Robert Chen, Stephen Cochi, William Egan, Susan Ellenberg, Jesse Goodman, Walt Orenstein, and Larry Pickering for their helpful ideas and insights about the issues raised in this article.
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Footnotes |
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Contributors
R. Bernier and K. Midthun conceived the ideas for this article. R. Bernier wrote the first draft, and both authors critiqued and rewrote portions of subsequent drafts.
Accepted for publication February 10, 2004.
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References |
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TOPABSTRACTINTRODUCTIONCURRENT SYSTEMTHE PROBLEM ACCORDING TO...THE PROPOSAL OF SALMON...MISREADING THE NRCTHE NRC POSITION IN...THE NRC POSITION IN...THE NRC FRAMEWORK FOR...BENEFITS OF THE CURRENT...POTENTIAL CONFLICTS OF INTERESTWHAT MORE COULD BE...References |
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1. Salmon DA, Moulton LH, Halsey NA. Enhancing Public Confidence in Vaccines Through Independent Oversight of Postlicensure Vaccine Safety. Am J Public Health. 2004;94:947–950.
2. National Research Council. Risk Assessment in the Federal Government: Managing the Process. Washington, DC: National Academy Press; 1983.
3. National Research Council. Understanding Risk: Informing Decisions in a Democratic Society. Washington, DC: National Academy Press; 1996.
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