Expert Review of Vaccines
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
Perspectives on the future of postmarket vaccine safety surveillance and evaluation Robert Ball To cite this article: Robert Ball (2014) Perspectives on the future of postmarket vaccine safety surveillance and evaluation, Expert Review of Vaccines, 13:4, 455-462 To link to this article: http://dx.doi.org/10.1586/14760584.2014.891941
Published online: 07 Mar 2014.
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Perspectives on the future of postmarket vaccine safety surveillance and evaluation Expert Rev. Vaccines 13(4), 455–462 (2014)
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Robert Ball Office of Biostatistics and Epidemiology, CBER, FDA, Rockville, MD, USA Tel.: +1 240 402 0397 Fax: +1 301 796 9832 [email protected]
Strong, scientifically-based postmarket safety surveillance is critical to maintaining public confidence in vaccinations and reducing the burden from vaccine-preventable diseases. The infrastructure and scientific methods for postmarket safety surveillance have continuously improved over the last 30 years, with major enhancements in the last decade. Supporting and enhancing this system will continue to be important as the number of vaccines and people vaccinated expands globally. KEYWORDS: benefit-risk • epidemiology • genomics • informatics • pharmacovigilance • surveillance • vaccine safety
Vaccination’s role in preventing infectious diseases globally is more important and successful than ever and will continue to expand with new vaccines on the horizon. Safety has always been a major focus of vaccine development, but vaccines like all medical products have some rare risks of adverse effects. As the incidence of vaccine-preventable diseases is reduced, concerns about vaccine safety increase among the public. A strong postmarket vaccine safety system is necessary to both ensure that vaccines are safe in actual use and to maintain the public’s confidence in vaccination. In the USA, the modern era of postmarketing vaccine safety began with the passage of the National Childhood Vaccine Injury Act of 1986. In the nearly 30 years since, the infrastructure and scientific methods for postmarketing safety have continuously improved in the USA and around the world. This paper will focus on improvements in the postmarket vaccine safety surveillance system over the past decade beginning with predictions made in 2002 [1]. In the 2002 paper, the predictions for the evolution of the vaccine safety system fell into two main categories: improvements in clinical trial and observational data infrastructure and analysis; and improvements in applying biological knowledge to vaccine safety surveillance. This paper will review whether those predictions have come to pass, identify other major trends in postmarket vaccine safety in the intervening years and suggest possibilities for future directions. informahealthcare.com
10.1586/14760584.2014.891941
Improvements in clinical trial & observational data infrastructure & analysis Clinical trials
While the focus of this paper is on the postmarket safety surveillance system, the characteristics of that system depend greatly on those of the premarket clinical trial system. In addition to surveillance for unexpected adverse events, unresolved safety signals observed in clinical trials, not sufficient to prevent licensure, should be evaluated post marketing. Practically speaking, the magnitude of the risks that need evaluation post marketing will depend on the size of clinical trials prior to marketing. In a November 2000 workshop [2], one of the points of debate was whether building a better postmarketing system could allow relatively smaller clinical trials prior to marketing. One viewpoint presented was that a system that could rapidly and rigorously evaluate safety in large population could also reduce the time spent in clinical development and speed disease preventing vaccines to the market and prevent much serious illness and death. An alternative perspective was that because of limitations of postmarketing regulatory authority, safety infrastructure, data quality and ability to make valid inferences using observational data, it would be better to improve the efficiency of large premarketing clinical trials by using simpler designs focused
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on safety. This led to the prediction that ‘clinical trials of new products, using simple designs focusing on safety, may routinely include 10,000–50,000 people’ [1]. Clinical trials and studies of new vaccines are generally larger than trials for new drugs, but with the notable exception of trials evaluating the risk of intussusception after rotavirus vaccines [3,4], there have been few large trials focused on specific safety outcomes. In addition, while the postmarket vaccine safety system’s ability to rapidly evaluate potential risks from new vaccines has improved greatly, as will be presented next, there are still enough limitations to that system that the question of the proper balance between premarket and postmarket safety data collection remains open. Observational data infrastructure & analysis
The current postmarket vaccine safety system relies on two main components: submission of spontaneous reports of adverse events by the public and healthcare providers to systems maintained by regulatory and public health authorities; and conduct of surveillance and epidemiological studies using populationbased data, increasingly consisting of electronic administrative claims and health records. While spontaneous reporting systems (SRSs), such as the US Vaccine Adverse Event Reporting System (VAERS), the European Eudrovigilance system or the WHO Uppsala Monitoring Centre’s Vigibase, have limitations for making causal inference about vaccines and adverse events [5], they continue to serve the important early warning function and to detect signals especially for rare adverse events. Much effort has been invested in improving the efficiency and validity of inferences obtained from these data. Spontaneous reporting systems
SRS play an important role in detecting serious unexpected adverse events and providing reassurance that no obvious safety problems have emerged soon after the introduction of a new vaccine [6] Given the limitations of SRS, the lack of safety signals soon after new vaccine introduction is not a guarantee of absolute safety, as was recently illustrated with the detection of narcolepsy after 2009 H1N1 influenza vaccine in Europe, almost a year after the vaccines were used. Efficient and rigorous analyses of spontaneous reports of adverse events following immunization remain a challenge despite improvements from the use of data mining methods [7]. Two complementary approaches are generally taken in review of spontaneous reports. One relies on statistical data mining of spontaneous reports based on medical product exposure–adverse event pairs and is highly automated but requires extensive human expert evaluation. The second and more traditional approach involves the description of a series of similar cases by experienced evaluators to identify unusual patterns in the key features of the case reports, especially the clinical and demographical characteristics, time to onset since exposure to the vaccine and alternative explanations for the adverse event [8]. The case series remain largely dependent on human experts with only limited automation. From the point of view of efficiency, the 456
increasing volume of reports precludes detailed case series review in the traditional manner for all but the most compelling issues. The case series framework, while structured, does not allow for rigorous statistical inference [9]. The observation of intussusception after RotaShield in VAERS provides a classic description of how a clinical case series analysis was used to identify a safety issue [10]. It is important to distinguish case series used in this classic clinical sense and formal selfcontrolled case only methods that have become popular [11]. Generally, these latter methods require unbiased ascertainment of cases with respect to vaccination, and since this assumption is violated in SRS, these methods of analysis are not usually recommended for SRS data. Observed versus expected analysis based on doses administered or distributed and background rates of the adverse event of interest [12] is also sometimes used, but is often difficult to interpret because of the assumptions made in the calculations. Broadly speaking, the introduction of statistical data mining was intended to improve both of these limitations. Lacking obvious alternatives, current statistical data mining algorithms use a variation of an observed to expected calculation based on the assumption that the accumulated case reports in a SRS database can be treated like a cohort for purposes of statistical analysis, even though they do not represent a cohort in a traditional epidemiological sense. It is well known that the biases present in SRS data are not easily overcome with statistical methods alone, so statistical methods have dealt primarily with other issues (e.g., confounding, multiple comparisons, sparseness of data). Most current statistical data mining methods are also limited in their ability to identify multidimensional patterns in the clinical features important in the case series approach. Despite these limitations, and with optimal strategies for data mining still in development, data mining is routinely used and has successfully identified a novel safety signal prior to its detection by other methods [13]. Population-based surveillance systems
The growth of population-based vaccine safety surveillance and epidemiological studies has been profound in the past decade with major new initiatives around the world along with advances in scientific methods. The overarching goal of efforts in this arena is to expand and improve the use of healthcare data to increase the power, speed and quality of vaccine safety monitoring after licensure. Reaching this goal requires improving both the infrastructure and methods for safety monitoring. In the USA, the CDC’s Vaccine Safety Datalink (VSD) [14] has worked for more than two decades pioneering the use of electronic health data for vaccine safety. In the past decade, the VSD pioneered the use of Rapid Cycle Analysis for near realtime surveillance of selected adverse events after newly introduced vaccines [15]. The US FDA worked with the Centers for Medicare and Medicaid Services [16] for more than a decade to use electronic claims data for monitoring safety of vaccination in the elderly, especially influenza vaccines. Other US government Expert Rev. Vaccines 13(4), (2014)
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Perspectives on the future of postmarket vaccine safety surveillance & evaluation
health data systems, including those of the Department of Defense and Veteran’s Administration, have also been used. A major advance in the USA came in 2007 with the passage of the FDA Amendments Act that required the development of a system for postmarketing medical product risk identification consisting of at least 100 million people. The FDA launched the Sentinel Initiative in response [17]. Shortly, thereafter in an independent effort to expand vaccine safety capabilities to monitor the 2009 H1N1 influenza vaccine, the Postlicensure Rapid Immunization Safety Monitoring (PRISM) program was created under the auspices of the US Department of Health and Human Services. In addition, enhanced collaborations among other government agencies with healthcare data were developed [18]. A novel real-time surveillance method that adjusted for delay in claims was put into use to monitor the 2009 H1N1 influenza vaccine [19]. The PRISM program was subsequently moved into the FDA’s Mini-Sentinel initiative and is being further developed into a general purpose vaccine safety surveillance system [20]. In Europe, similar surveillance systems were developed to monitor the safety of the 2009 H1N1 vaccine including the VAESCO project and activities in individual countries [21]. The safety signal of narcolepsy after the adjuvanted 2009 H1N1 influenza vaccines was detected by a network of specialist physicians and subsequently evaluated in population-based systems [22]. In addition, efforts to bring together data from many countries using a novel case-based method hold promise for a Global VSD [23]. Improvements in data architecture (e.g., use of electronic medical records in vaccine safety surveillance), methods for near real-time surveillance and conducting definitive studies with rigorous case definitions in an efficient manner will be needed to bring this vision to fruition. Improvement in applying biological knowledge to vaccine safety surveillance
Three of the predictions from 2002 [1] focused on application of knowledge of the biological aspects of adverse effects to improve vaccine safety, but there has been limited progress in this area. An excellent example of the consequences of the lack of improved understanding of biological mechanisms of vaccine adverse effects is Guillain Barre´ syndrome (GBS) after the 1976 ‘swine flu’ vaccine. This lack of knowledge has led to the requirement for extensive surveillance each influenza season of hundreds of millions of people. If GBS recurs, as it did after the 2009 H1N1 influenza vaccine [24], then it is usually detected after the fact. Better understanding of the mechanisms of action would allow implementation of prevention strategies, whether in vaccine design, manufacturing, screening of at-risk populations, or targeted surveillance. The completion of the Human Genome Project and use of rapidly evolving high-throughput technology have created high expectations for the field of personalized medicine. There have been consistent suggestions to apply these technologies to vaccination [25], including the coining of the term ‘vaccinomics’ to describe this emerging field [26]. Evaluation of genetic predictors informahealthcare.com
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of vaccine effectiveness has been more common than vaccine safety [1,26], but there has been more recent application to the safety of smallpox and Lyme vaccines [27,28]. The latter study also demonstrated the potential for SRS to serve as a source of cases of rare adverse events for evaluation of genetic risk factors, a strategy that is being applied in ongoing studies of adverse effects after Measles–Mumps–Rubella vaccine by the FDA. A comprehensive strategy for applying genomics has been slow to develop in part because of the rapidly evolving science of genomics, the rarity of vaccine adverse effects and lack of a clear approach to personalized vaccination. What other trends in vaccine safety have been apparent in the last decade? What’s old is new again
While new vaccines introduced into the market receive intense scrutiny by regulatory and public health authorities, older vaccines continue to demand attention as the public raises new concerns. This is perhaps best illustrated by the intense public concern raised about Measles–Mumps–Rubella vaccines and thimerosal in vaccines and autism. Numerous studies demonstrating the safety of these vaccines were required in the last 10 years to reassure the public [29]. GBS was observed after the 1976 ‘swine flu’ vaccine and has been carefully studied in the intervening years [30]. The issue again gained prominence with the use of the 2009 H1N1 influenza vaccines and led to the development of large-scale population-based systems to monitor the safety of the vaccine (previously discussed), which detected a small increased risk of GBS [24]. In 1998, the Rotashield vaccine was voluntarily withdrawn from the market after it was associated with intussusception [31]. New rotavirus vaccines were introduced in the last decade after very large clinical trials ruled out a risk of intussusception of the same magnitude as Rotashield [3,4]. Global surveillance of these vaccines detected a much smaller increased risk and a benefit–risk analysis remains favorable to the vaccine [32,33]. Another recent example that illustrates the need to monitor vaccines with established safety profiles is the emergence of an increased risk of febrile seizures following Commonwealth Serum Laboratories (CSL) influenza vaccine in Australia in 2010 [34]. These observations all point out that continuous vigilance of existing vaccines is necessary to ensure safety and maintain public confidence in vaccination. Vaccine safety has become even more global
The Global Vaccine Action Plan is a framework approved by the World Health Assembly in May 2012 to improve health by extending the full benefits of immunization to all people [35]. Vaccine safety surveillance and research will be an important part of this effort [36,37]. Vaccines have long been used globally but over the past decade the desire to first introduce new vaccines in low- and middle-income countries (LMIC), where the disease burden is highest, but the safety surveillance system is weakest, led to the recognition that a new approach was needed. Rumors about vaccine safety spread very rapidly and need to be rigorously investigated and transparently 457
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communicated no matter where they occur. New vaccines for tropical diseases like malaria and dengue will require welldesigned postmarket pharmacovigilance plans both because of the novel designs of the vaccines and their likely first use in LMIC. To respond to this landscape, the WHO undertook a process to develop a blueprint for global vaccine safety that led to the launching of the Global Vaccine Safety Initiative. The Global Vaccine Safety Initiative is a framework of strategic objectives for enhancing global vaccine safety. The strategic objectives focus on building and supporting vaccine pharmacovigilance in LMIC. The eight strategic objectives include Adverse Event Following Immunization (AEFI) detection, investigation of safety signals, vaccine safety communitation, tools and methods, a regulatory framework, technical support and training, global analysis and response and public–private information exchange [38]. Advances in communication technology & informatics
While electronic database systems have been in use to evaluate vaccine safety in the USA for more than 20 years, and electronic submission of individual case safety reports is now global through the WHO’s Uppsala Monitoring Center, new mobile phone, social media and informatics technologies have only begun to be investigated for their value in vaccine safety. These technologies might facilitate the surveillance for emerging safety issues and public concerns faster than traditional pharmacovigilance processes. These technologies might also facilitate responding to public concerns in a more timely way [39]. They also offer the potential for centralized or regionalized data collection and analysis in LMIC that would make the pharmacovigilance process more efficient. Expert commentary
The postmarketing vaccine safety system has made major improvements over the past decade although the improvements have occurred unevenly. Scientifically, major advances have been made in methods of surveillance using electronic data sources. Major infrastructure improvements have been made in some countries, but the global infrastructure lags behind. There have been fewer advances in understanding the pathophysiology of vaccine adverse effects. The global postmarketing vaccine safety system remains fragmented both in terms of a conceptual framework and implementation. While resource constraints are the main driver of the limitations of the system in LMIC, lack of consensus around a rigorous scientific framework in which to view postmarketing vaccine safety remains an overarching concern. The advent of social media and mobile devices globally offers challenge and promise for improving surveillance and communication about postmarketing vaccine safety. Major initiatives have been launched to further improve the current state, and the next decade is likely to see further improvements if these initiatives are fully supported. Five-year view
An important trend which will continue is the recognition that vaccine safety surveillance requires a systems and benefit–risk 458
perspective. The performance characteristics of each element of the system, including clinical trials, SRS, population-based surveillance and other epidemiological studies, and new aspects like mobile communications, social media and person-generated internet data, need to be understood and integrated with emerging biological knowledge of vaccine adverse events. In addition, an integrated analysis of the performance of the system as a whole needs to be undertaken, so the components can better be used like tools in a toolbox to meet evolving scientific needs and public expectations to optimize vaccination to prevent disease. A systems & benefit–risk perspective on vaccine safety surveillance throughout the lifecycle
As was discussed at the beginning of this article, the optimal balance between pre- and postmarket safety data collection remains an open question. One approach to developing a more integrated perspective on this question is to evaluate the need for safety information in the context of the benefit of the vaccine. A theoretically optimal framework for deciding how much data are needed at each phase of the lifecycle has been lacking, but simulation of the vaccine development lifecycle in the context of vaccine benefit and risk has been proposed to solve this problem. For example, recent work linking infectious disease transmission and game theory models has allowed the systematic exploration of the interplay between disease risk and vaccine safety and effectiveness in vaccination decision making [40]. The findings of this initial effort indicate that for vaccine disease situations where disease risk and vaccine efficacy are sufficiently high, individuals may be more willing to tolerate greater uncertainty in vaccine safety in the early years of an immunization program. In such a situation, shifting more safety data collection to the postmarketing phase, assuming rigorous high-quality studies can be rapidly conducted, might be reasonable. These models have been extended to show that public education on vaccine safety and infection risk is a key to maintaining vaccination levels that are sufficient for herd immunity [41]. Additional research in both the structure of the mathematical models and what constitutes acceptable vaccine risk is needed to advance this work. In the USA, the FDA has launched a pilot project to evaluate a structured, but not quantitative, approach to benefit–risk evaluation for drugs and biologic products [42]. In Europe, the Innovation in Medicine Initiative has begun project Advance to build a framework in Europe to rapidly deliver data on the benefits and risks of vaccines in actual use [43]. ‘Adaptive licensing’, which aims to streamline premarket development by taking a lifecycle perspective on the benefits and risks of a medical product by ensuring robust postmarket safety and effectiveness evaluation in the context of increased regulatory flexibility, is being tested in Europe [44], but remains controversial [45]. Improvements in all of the components of the safety monitoring system will be needed to bring any comprehensive benefit–risk evaluation framework to fruition, as will be discussed next. Expert Rev. Vaccines 13(4), (2014)
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Improving the efficiency & rigor of SRS
Improving the evaluation of spontaneous reports continues to be an important goal and is an active area of research. The first step in optimizing the performance of SRS involves improving the quality of reports rather than increasing the number of reports. Minimal requirements for a case report include an identifiable patient, reporter, suspect vaccine, and adverse event. But such a limited amount of information is rarely useful alone since details about a person’s age, gender, past medical history, concomitant vaccine, drug and other exposures, as well as the time course relative to the suspect exposure, and clinical description of the adverse event, are usually necessary to identify patterns of interest. Reporters should be encouraged to obtain as much of this information as possible and might be facilitated through greater involvement of patients in reporting as is encouraged in some jurisdictions. Automating the analysis process to make it both more efficient and more accurate is in part dependent on improved data quality. This is especially salient in light of globalization of adverse event (AE) reporting, and the advent of population-based systems that allow rapid and rigorous assessments of safety issues. As mining of populationbased data becomes feasible, it will be more likely that rare and even delayed onset adverse events are detected in such systems. As this transition occurs, it will be ever more important for SRS to be populated with high-quality data, submitted by astute clinicians and patients who will allow signal generation for rare adverse events before sufficient data accrue in population-based systems and rigorous statistical inferences can be made. Research in ways to submit reports (see next section), data mining and visualization will be important. While optimizing current data mining approaches is useful, the field would also benefit from alternative strategies. One such novel strategy involves going ‘back to the future’ to combine the inspiration of the astute clinical observation with the power of medical informatics and statistics and aims to create a decision support environment that will better use the expertise of human medical experts by automating and summarizing case report data in a manner more analogous to human cognitive processes. At the heart of this endeavor is a case-based reasoning framework [46]. The key organizing principle in the application of case-based reasoning is the identification of ‘similar’ cases, defined using quantitative metrics adapted from the field of information retrieval [47]. As applied to SRS, this could mean: finding cases ‘similar’ to an ideal case definition [48], a published case report [49] or an index case reported to the SRS; summarizing the key features of such cases, including the most likely diagnosis, the time to onset after exposure to the vaccine and alternative explanations for the diagnosis, and clustering by location (e.g., single clinic) [50]; inferring whether groups of ‘similar’ cases occur more commonly than expected within the SRS using both algorithmic and statistical methods [51,52]; and presenting this information to the expert reviewer in an intuitively appealing manner. While currently identifying similar cases relies primarily on application of case definitions by medical experts, advances informahealthcare.com
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in informatics might allow for automation of some or all of this work. Improvements in statistical methods of inference from SRSs are also needed. Mining social media, user-generated internet data & mobile communications
The mining of social media for public health information has received attention recently because of the success of ‘Google flu trends’ [53] in identifying influenza transmission and the identification of drug–drug interactions from patient-generated internet data [54,55]. Vaccine safety issues are discussed on internet blogs and Twitter but most such discussions lack the necessary details typically used for case series evaluations. Whether aggregating the information would allow those who monitor vaccine safety to take advantage of the ‘wisdom of the crowd’ remains to be fully evaluated [56]. Key issues in this evaluation are whether such approaches might provide earlier warning of emerging safety concerns or identify geographically localized clusters for regulators and public health authorities. Such approaches might be useful in settings where no or weak SRS are present or to reduce the cost of vaccine safety surveillance, but these hypotheses remain to be demonstrated. Traditional SRSs are resource intensive but there might be an opportunity to use mobile phones to allow health professionals to inexpensively send an alert to a central monitoring point regarding adverse events [57]. The collation, investigation and analysis of such reports remain a challenge, but might be facilitated by both new analytic strategies and the development of regional networks. Population-based system infrastructure & methods development
The continued expansion and refinement of the infrastructure allowing for evaluation of vaccine safety concerns in large populations are likely to continue. The adoption of electronic medical records on a wide scale should lead to improvements in the efficiency and quality of data available for assessments. But improvements in the backbone electronic health data systems alone will not be sufficient as they will need to be linked to vaccination and other registries that contain data not available in the core systems. These improvements should allow better assessments of vaccine safety in pregnancy and other special populations. While large countries and political entities like the USA, the EU and China will likely have sufficient resources and populations to build stand-alone systems, it will be important for smaller countries to build regional networks and to have a comprehensive description of vaccine distribution to facilitate sharing of vaccine safety information across countries and regions. The continued development and improvement of methods for vaccine safety surveillance are another area of growth. The last decade has seen the expanded use of a variety of selfcontrolled and near real-time methods for safety studies and surveillance. Assessment of potential bias in observational data, signal detection in population-based systems and quantitative 459
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benefit–risk analysis are areas likely to see real improvements. Worth noting is the work conducted by the Observational Medical Outcomes Partnership in applying the concept of evidence-based epidemiology to pharmacoepidemiological methods for drug safety [58], but the implications of this work for vaccine safety surveillance have not yet been explored. Because of this greater reliance on observational data and epidemiological assessment in both drug and vaccine safety assessment, there is likely to be a convergence of vaccine safety, drug safety and product quality surveillance systems [59]. These systems will come to rely on the same informatics and communication backbone and use similar analytic strategies, still informed by the experts in the particular disciplines. This might result in efficiencies and linkages that were heretofore unobtainable. One might even envision a system in which aggregation of large numbers of ‘tweets’ with only the minimal data elements previously described provide an early alert which is assessed using higher quality reports from SRSs and data about product and lot quality, while sufficient data accumulate in population-based systems for rigorous evaluations to be conducted. Pathogenesis of vaccine AEs & personalized vaccination
The pathogenesis of many adverse events will likely become better understood and linked to specific genetic profiles as a result of major investments in understanding disease pathogenesis in general and vaccination in particular. Personalized vaccination will become theoretically possible as the cost of generating genetic profiles is reduced. This will lead to major challenges to the current paradigm of population-based vaccination and new approaches to vaccine safety focused on either vaccine modification or individual exclusions based on genetic profiles might be needed. Recognizing the complexity of this undertaking, two major initiatives have been started. In Europe, the Innovative Medicines Initiative has launched project BioVaxSafe, and in the USA, the National Institutes of Allergy
and Infectious Diseases has launched several major initiatives to better understand the immune response to vaccination including adjuvants. While there has been growing interest in utilizing genomic information to predict safety and efficacy in clinical trials, most serious adverse effects caused by vaccines are rare and currently can only be studied in the postmarketing period after large numbers of people are vaccinated. Identifying and understanding host factors that predispose to these adverse effects could help to clarify whether they are a result of a genetic predisposition. Creation of a repository of tissue specimens from people who have experienced adverse effects after vaccination has been proposed as a means of making the process of studying genomic risk factors more efficient, but has proven difficult. Building such a repository would constitute an important step toward comprehensive understanding and helping to prevent these adverse effects. Future ‘personalization’ of vaccine safety is largely contingent on advances in genomic science generally, especially the ability to inexpensively provide individuals with their genetic sequence. Ultimately, this knowledge may help to maintain the public’s confidence in vaccines, provide more complete evidence for rational vaccination polices, guide development of safer vaccines and further protect public health. Financial & competing interests disclosure
This article reflects the views of the author and should not be construed to represent FDA’s views or policies. This work was supported as part of the author’s duties as an employee of the US FDA. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Vaccination will be more important than ever as a disease prevention strategy as more vaccines are introduced and more people are vaccinated globally. • Vaccination is very safe but rare adverse effects do occur. • Declining vaccine-preventable disease incidence leads to increased public demands for evidence of vaccine safety. • Pathogenesis of many adverse events will become better understood and linked to specific genetic profiles aided by the collection of tissue samples in adverse event biorepositories. • Personalized vaccination will become theoretically possible as the cost of generating genetic profiles is reduced. • Postmarketing surveillance coupled with epidemiological studies are necessary to monitor vaccine safety in actual use and improvements in methods will continue. • New technologies, especially informatics, internet and mobile communications, will be evaluated and integrated into vaccines safety surveillance system. • Convergence of vaccine safety, drug safety and product quality surveillance systems will increase. • Vaccines will become even safer and vaccination will thrive as a disease prevention strategy.
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Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
Ball R. Methods for ensuring vaccine safety. Expert Rev Vaccines 2002;1:161-8
2.
Ellenberg SS, Foulkes MA, Midthun KM, Goldenthal KL. Evaluating the safety of new vaccines: summary of a workshop. Am J Public Health 2005;95(5):800-7
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An excellent description of the strengths and weaknesses of spontaneous reporting systems for vaccine safety.
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Dal Pan GJ, Lindquist M, Gelperin K. Postmarketing spontaneous pharmacovigilance reporting systems. In: Strom BL, Kimmel SE, Hennessy S, editors. Pharmacoepidemiology. 5th Edition. John Wiley and Sons, LTD; Oxford, UK: 2012. p. 137-57
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CDC. Intussusception among recipients of rotavirus vaccine – United States, 1998-1999. MMWR 1999;48:577-81
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Provides background rates for many adverse events that occur coincidentally after vaccination.
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Expert Rev. Vaccines 13(4), (2014)
ISSN: 1476-0584 (Print) 1744-8395 (Online) Journal homepage: http://www.tandfonline.com/loi/ierv20
Perspectives on the future of postmarket vaccine safety surveillance and evaluation Robert Ball To cite this article: Robert Ball (2014) Perspectives on the future of postmarket vaccine safety surveillance and evaluation, Expert Review of Vaccines, 13:4, 455-462 To link to this article: http://dx.doi.org/10.1586/14760584.2014.891941
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Perspectives on the future of postmarket vaccine safety surveillance and evaluation Expert Rev. Vaccines 13(4), 455–462 (2014)
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Robert Ball Office of Biostatistics and Epidemiology, CBER, FDA, Rockville, MD, USA Tel.: +1 240 402 0397 Fax: +1 301 796 9832 [email protected]
Strong, scientifically-based postmarket safety surveillance is critical to maintaining public confidence in vaccinations and reducing the burden from vaccine-preventable diseases. The infrastructure and scientific methods for postmarket safety surveillance have continuously improved over the last 30 years, with major enhancements in the last decade. Supporting and enhancing this system will continue to be important as the number of vaccines and people vaccinated expands globally. KEYWORDS: benefit-risk • epidemiology • genomics • informatics • pharmacovigilance • surveillance • vaccine safety
Vaccination’s role in preventing infectious diseases globally is more important and successful than ever and will continue to expand with new vaccines on the horizon. Safety has always been a major focus of vaccine development, but vaccines like all medical products have some rare risks of adverse effects. As the incidence of vaccine-preventable diseases is reduced, concerns about vaccine safety increase among the public. A strong postmarket vaccine safety system is necessary to both ensure that vaccines are safe in actual use and to maintain the public’s confidence in vaccination. In the USA, the modern era of postmarketing vaccine safety began with the passage of the National Childhood Vaccine Injury Act of 1986. In the nearly 30 years since, the infrastructure and scientific methods for postmarketing safety have continuously improved in the USA and around the world. This paper will focus on improvements in the postmarket vaccine safety surveillance system over the past decade beginning with predictions made in 2002 [1]. In the 2002 paper, the predictions for the evolution of the vaccine safety system fell into two main categories: improvements in clinical trial and observational data infrastructure and analysis; and improvements in applying biological knowledge to vaccine safety surveillance. This paper will review whether those predictions have come to pass, identify other major trends in postmarket vaccine safety in the intervening years and suggest possibilities for future directions. informahealthcare.com
10.1586/14760584.2014.891941
Improvements in clinical trial & observational data infrastructure & analysis Clinical trials
While the focus of this paper is on the postmarket safety surveillance system, the characteristics of that system depend greatly on those of the premarket clinical trial system. In addition to surveillance for unexpected adverse events, unresolved safety signals observed in clinical trials, not sufficient to prevent licensure, should be evaluated post marketing. Practically speaking, the magnitude of the risks that need evaluation post marketing will depend on the size of clinical trials prior to marketing. In a November 2000 workshop [2], one of the points of debate was whether building a better postmarketing system could allow relatively smaller clinical trials prior to marketing. One viewpoint presented was that a system that could rapidly and rigorously evaluate safety in large population could also reduce the time spent in clinical development and speed disease preventing vaccines to the market and prevent much serious illness and death. An alternative perspective was that because of limitations of postmarketing regulatory authority, safety infrastructure, data quality and ability to make valid inferences using observational data, it would be better to improve the efficiency of large premarketing clinical trials by using simpler designs focused
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on safety. This led to the prediction that ‘clinical trials of new products, using simple designs focusing on safety, may routinely include 10,000–50,000 people’ [1]. Clinical trials and studies of new vaccines are generally larger than trials for new drugs, but with the notable exception of trials evaluating the risk of intussusception after rotavirus vaccines [3,4], there have been few large trials focused on specific safety outcomes. In addition, while the postmarket vaccine safety system’s ability to rapidly evaluate potential risks from new vaccines has improved greatly, as will be presented next, there are still enough limitations to that system that the question of the proper balance between premarket and postmarket safety data collection remains open. Observational data infrastructure & analysis
The current postmarket vaccine safety system relies on two main components: submission of spontaneous reports of adverse events by the public and healthcare providers to systems maintained by regulatory and public health authorities; and conduct of surveillance and epidemiological studies using populationbased data, increasingly consisting of electronic administrative claims and health records. While spontaneous reporting systems (SRSs), such as the US Vaccine Adverse Event Reporting System (VAERS), the European Eudrovigilance system or the WHO Uppsala Monitoring Centre’s Vigibase, have limitations for making causal inference about vaccines and adverse events [5], they continue to serve the important early warning function and to detect signals especially for rare adverse events. Much effort has been invested in improving the efficiency and validity of inferences obtained from these data. Spontaneous reporting systems
SRS play an important role in detecting serious unexpected adverse events and providing reassurance that no obvious safety problems have emerged soon after the introduction of a new vaccine [6] Given the limitations of SRS, the lack of safety signals soon after new vaccine introduction is not a guarantee of absolute safety, as was recently illustrated with the detection of narcolepsy after 2009 H1N1 influenza vaccine in Europe, almost a year after the vaccines were used. Efficient and rigorous analyses of spontaneous reports of adverse events following immunization remain a challenge despite improvements from the use of data mining methods [7]. Two complementary approaches are generally taken in review of spontaneous reports. One relies on statistical data mining of spontaneous reports based on medical product exposure–adverse event pairs and is highly automated but requires extensive human expert evaluation. The second and more traditional approach involves the description of a series of similar cases by experienced evaluators to identify unusual patterns in the key features of the case reports, especially the clinical and demographical characteristics, time to onset since exposure to the vaccine and alternative explanations for the adverse event [8]. The case series remain largely dependent on human experts with only limited automation. From the point of view of efficiency, the 456
increasing volume of reports precludes detailed case series review in the traditional manner for all but the most compelling issues. The case series framework, while structured, does not allow for rigorous statistical inference [9]. The observation of intussusception after RotaShield in VAERS provides a classic description of how a clinical case series analysis was used to identify a safety issue [10]. It is important to distinguish case series used in this classic clinical sense and formal selfcontrolled case only methods that have become popular [11]. Generally, these latter methods require unbiased ascertainment of cases with respect to vaccination, and since this assumption is violated in SRS, these methods of analysis are not usually recommended for SRS data. Observed versus expected analysis based on doses administered or distributed and background rates of the adverse event of interest [12] is also sometimes used, but is often difficult to interpret because of the assumptions made in the calculations. Broadly speaking, the introduction of statistical data mining was intended to improve both of these limitations. Lacking obvious alternatives, current statistical data mining algorithms use a variation of an observed to expected calculation based on the assumption that the accumulated case reports in a SRS database can be treated like a cohort for purposes of statistical analysis, even though they do not represent a cohort in a traditional epidemiological sense. It is well known that the biases present in SRS data are not easily overcome with statistical methods alone, so statistical methods have dealt primarily with other issues (e.g., confounding, multiple comparisons, sparseness of data). Most current statistical data mining methods are also limited in their ability to identify multidimensional patterns in the clinical features important in the case series approach. Despite these limitations, and with optimal strategies for data mining still in development, data mining is routinely used and has successfully identified a novel safety signal prior to its detection by other methods [13]. Population-based surveillance systems
The growth of population-based vaccine safety surveillance and epidemiological studies has been profound in the past decade with major new initiatives around the world along with advances in scientific methods. The overarching goal of efforts in this arena is to expand and improve the use of healthcare data to increase the power, speed and quality of vaccine safety monitoring after licensure. Reaching this goal requires improving both the infrastructure and methods for safety monitoring. In the USA, the CDC’s Vaccine Safety Datalink (VSD) [14] has worked for more than two decades pioneering the use of electronic health data for vaccine safety. In the past decade, the VSD pioneered the use of Rapid Cycle Analysis for near realtime surveillance of selected adverse events after newly introduced vaccines [15]. The US FDA worked with the Centers for Medicare and Medicaid Services [16] for more than a decade to use electronic claims data for monitoring safety of vaccination in the elderly, especially influenza vaccines. Other US government Expert Rev. Vaccines 13(4), (2014)
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Perspectives on the future of postmarket vaccine safety surveillance & evaluation
health data systems, including those of the Department of Defense and Veteran’s Administration, have also been used. A major advance in the USA came in 2007 with the passage of the FDA Amendments Act that required the development of a system for postmarketing medical product risk identification consisting of at least 100 million people. The FDA launched the Sentinel Initiative in response [17]. Shortly, thereafter in an independent effort to expand vaccine safety capabilities to monitor the 2009 H1N1 influenza vaccine, the Postlicensure Rapid Immunization Safety Monitoring (PRISM) program was created under the auspices of the US Department of Health and Human Services. In addition, enhanced collaborations among other government agencies with healthcare data were developed [18]. A novel real-time surveillance method that adjusted for delay in claims was put into use to monitor the 2009 H1N1 influenza vaccine [19]. The PRISM program was subsequently moved into the FDA’s Mini-Sentinel initiative and is being further developed into a general purpose vaccine safety surveillance system [20]. In Europe, similar surveillance systems were developed to monitor the safety of the 2009 H1N1 vaccine including the VAESCO project and activities in individual countries [21]. The safety signal of narcolepsy after the adjuvanted 2009 H1N1 influenza vaccines was detected by a network of specialist physicians and subsequently evaluated in population-based systems [22]. In addition, efforts to bring together data from many countries using a novel case-based method hold promise for a Global VSD [23]. Improvements in data architecture (e.g., use of electronic medical records in vaccine safety surveillance), methods for near real-time surveillance and conducting definitive studies with rigorous case definitions in an efficient manner will be needed to bring this vision to fruition. Improvement in applying biological knowledge to vaccine safety surveillance
Three of the predictions from 2002 [1] focused on application of knowledge of the biological aspects of adverse effects to improve vaccine safety, but there has been limited progress in this area. An excellent example of the consequences of the lack of improved understanding of biological mechanisms of vaccine adverse effects is Guillain Barre´ syndrome (GBS) after the 1976 ‘swine flu’ vaccine. This lack of knowledge has led to the requirement for extensive surveillance each influenza season of hundreds of millions of people. If GBS recurs, as it did after the 2009 H1N1 influenza vaccine [24], then it is usually detected after the fact. Better understanding of the mechanisms of action would allow implementation of prevention strategies, whether in vaccine design, manufacturing, screening of at-risk populations, or targeted surveillance. The completion of the Human Genome Project and use of rapidly evolving high-throughput technology have created high expectations for the field of personalized medicine. There have been consistent suggestions to apply these technologies to vaccination [25], including the coining of the term ‘vaccinomics’ to describe this emerging field [26]. Evaluation of genetic predictors informahealthcare.com
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of vaccine effectiveness has been more common than vaccine safety [1,26], but there has been more recent application to the safety of smallpox and Lyme vaccines [27,28]. The latter study also demonstrated the potential for SRS to serve as a source of cases of rare adverse events for evaluation of genetic risk factors, a strategy that is being applied in ongoing studies of adverse effects after Measles–Mumps–Rubella vaccine by the FDA. A comprehensive strategy for applying genomics has been slow to develop in part because of the rapidly evolving science of genomics, the rarity of vaccine adverse effects and lack of a clear approach to personalized vaccination. What other trends in vaccine safety have been apparent in the last decade? What’s old is new again
While new vaccines introduced into the market receive intense scrutiny by regulatory and public health authorities, older vaccines continue to demand attention as the public raises new concerns. This is perhaps best illustrated by the intense public concern raised about Measles–Mumps–Rubella vaccines and thimerosal in vaccines and autism. Numerous studies demonstrating the safety of these vaccines were required in the last 10 years to reassure the public [29]. GBS was observed after the 1976 ‘swine flu’ vaccine and has been carefully studied in the intervening years [30]. The issue again gained prominence with the use of the 2009 H1N1 influenza vaccines and led to the development of large-scale population-based systems to monitor the safety of the vaccine (previously discussed), which detected a small increased risk of GBS [24]. In 1998, the Rotashield vaccine was voluntarily withdrawn from the market after it was associated with intussusception [31]. New rotavirus vaccines were introduced in the last decade after very large clinical trials ruled out a risk of intussusception of the same magnitude as Rotashield [3,4]. Global surveillance of these vaccines detected a much smaller increased risk and a benefit–risk analysis remains favorable to the vaccine [32,33]. Another recent example that illustrates the need to monitor vaccines with established safety profiles is the emergence of an increased risk of febrile seizures following Commonwealth Serum Laboratories (CSL) influenza vaccine in Australia in 2010 [34]. These observations all point out that continuous vigilance of existing vaccines is necessary to ensure safety and maintain public confidence in vaccination. Vaccine safety has become even more global
The Global Vaccine Action Plan is a framework approved by the World Health Assembly in May 2012 to improve health by extending the full benefits of immunization to all people [35]. Vaccine safety surveillance and research will be an important part of this effort [36,37]. Vaccines have long been used globally but over the past decade the desire to first introduce new vaccines in low- and middle-income countries (LMIC), where the disease burden is highest, but the safety surveillance system is weakest, led to the recognition that a new approach was needed. Rumors about vaccine safety spread very rapidly and need to be rigorously investigated and transparently 457
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communicated no matter where they occur. New vaccines for tropical diseases like malaria and dengue will require welldesigned postmarket pharmacovigilance plans both because of the novel designs of the vaccines and their likely first use in LMIC. To respond to this landscape, the WHO undertook a process to develop a blueprint for global vaccine safety that led to the launching of the Global Vaccine Safety Initiative. The Global Vaccine Safety Initiative is a framework of strategic objectives for enhancing global vaccine safety. The strategic objectives focus on building and supporting vaccine pharmacovigilance in LMIC. The eight strategic objectives include Adverse Event Following Immunization (AEFI) detection, investigation of safety signals, vaccine safety communitation, tools and methods, a regulatory framework, technical support and training, global analysis and response and public–private information exchange [38]. Advances in communication technology & informatics
While electronic database systems have been in use to evaluate vaccine safety in the USA for more than 20 years, and electronic submission of individual case safety reports is now global through the WHO’s Uppsala Monitoring Center, new mobile phone, social media and informatics technologies have only begun to be investigated for their value in vaccine safety. These technologies might facilitate the surveillance for emerging safety issues and public concerns faster than traditional pharmacovigilance processes. These technologies might also facilitate responding to public concerns in a more timely way [39]. They also offer the potential for centralized or regionalized data collection and analysis in LMIC that would make the pharmacovigilance process more efficient. Expert commentary
The postmarketing vaccine safety system has made major improvements over the past decade although the improvements have occurred unevenly. Scientifically, major advances have been made in methods of surveillance using electronic data sources. Major infrastructure improvements have been made in some countries, but the global infrastructure lags behind. There have been fewer advances in understanding the pathophysiology of vaccine adverse effects. The global postmarketing vaccine safety system remains fragmented both in terms of a conceptual framework and implementation. While resource constraints are the main driver of the limitations of the system in LMIC, lack of consensus around a rigorous scientific framework in which to view postmarketing vaccine safety remains an overarching concern. The advent of social media and mobile devices globally offers challenge and promise for improving surveillance and communication about postmarketing vaccine safety. Major initiatives have been launched to further improve the current state, and the next decade is likely to see further improvements if these initiatives are fully supported. Five-year view
An important trend which will continue is the recognition that vaccine safety surveillance requires a systems and benefit–risk 458
perspective. The performance characteristics of each element of the system, including clinical trials, SRS, population-based surveillance and other epidemiological studies, and new aspects like mobile communications, social media and person-generated internet data, need to be understood and integrated with emerging biological knowledge of vaccine adverse events. In addition, an integrated analysis of the performance of the system as a whole needs to be undertaken, so the components can better be used like tools in a toolbox to meet evolving scientific needs and public expectations to optimize vaccination to prevent disease. A systems & benefit–risk perspective on vaccine safety surveillance throughout the lifecycle
As was discussed at the beginning of this article, the optimal balance between pre- and postmarket safety data collection remains an open question. One approach to developing a more integrated perspective on this question is to evaluate the need for safety information in the context of the benefit of the vaccine. A theoretically optimal framework for deciding how much data are needed at each phase of the lifecycle has been lacking, but simulation of the vaccine development lifecycle in the context of vaccine benefit and risk has been proposed to solve this problem. For example, recent work linking infectious disease transmission and game theory models has allowed the systematic exploration of the interplay between disease risk and vaccine safety and effectiveness in vaccination decision making [40]. The findings of this initial effort indicate that for vaccine disease situations where disease risk and vaccine efficacy are sufficiently high, individuals may be more willing to tolerate greater uncertainty in vaccine safety in the early years of an immunization program. In such a situation, shifting more safety data collection to the postmarketing phase, assuming rigorous high-quality studies can be rapidly conducted, might be reasonable. These models have been extended to show that public education on vaccine safety and infection risk is a key to maintaining vaccination levels that are sufficient for herd immunity [41]. Additional research in both the structure of the mathematical models and what constitutes acceptable vaccine risk is needed to advance this work. In the USA, the FDA has launched a pilot project to evaluate a structured, but not quantitative, approach to benefit–risk evaluation for drugs and biologic products [42]. In Europe, the Innovation in Medicine Initiative has begun project Advance to build a framework in Europe to rapidly deliver data on the benefits and risks of vaccines in actual use [43]. ‘Adaptive licensing’, which aims to streamline premarket development by taking a lifecycle perspective on the benefits and risks of a medical product by ensuring robust postmarket safety and effectiveness evaluation in the context of increased regulatory flexibility, is being tested in Europe [44], but remains controversial [45]. Improvements in all of the components of the safety monitoring system will be needed to bring any comprehensive benefit–risk evaluation framework to fruition, as will be discussed next. Expert Rev. Vaccines 13(4), (2014)
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Improving the efficiency & rigor of SRS
Improving the evaluation of spontaneous reports continues to be an important goal and is an active area of research. The first step in optimizing the performance of SRS involves improving the quality of reports rather than increasing the number of reports. Minimal requirements for a case report include an identifiable patient, reporter, suspect vaccine, and adverse event. But such a limited amount of information is rarely useful alone since details about a person’s age, gender, past medical history, concomitant vaccine, drug and other exposures, as well as the time course relative to the suspect exposure, and clinical description of the adverse event, are usually necessary to identify patterns of interest. Reporters should be encouraged to obtain as much of this information as possible and might be facilitated through greater involvement of patients in reporting as is encouraged in some jurisdictions. Automating the analysis process to make it both more efficient and more accurate is in part dependent on improved data quality. This is especially salient in light of globalization of adverse event (AE) reporting, and the advent of population-based systems that allow rapid and rigorous assessments of safety issues. As mining of populationbased data becomes feasible, it will be more likely that rare and even delayed onset adverse events are detected in such systems. As this transition occurs, it will be ever more important for SRS to be populated with high-quality data, submitted by astute clinicians and patients who will allow signal generation for rare adverse events before sufficient data accrue in population-based systems and rigorous statistical inferences can be made. Research in ways to submit reports (see next section), data mining and visualization will be important. While optimizing current data mining approaches is useful, the field would also benefit from alternative strategies. One such novel strategy involves going ‘back to the future’ to combine the inspiration of the astute clinical observation with the power of medical informatics and statistics and aims to create a decision support environment that will better use the expertise of human medical experts by automating and summarizing case report data in a manner more analogous to human cognitive processes. At the heart of this endeavor is a case-based reasoning framework [46]. The key organizing principle in the application of case-based reasoning is the identification of ‘similar’ cases, defined using quantitative metrics adapted from the field of information retrieval [47]. As applied to SRS, this could mean: finding cases ‘similar’ to an ideal case definition [48], a published case report [49] or an index case reported to the SRS; summarizing the key features of such cases, including the most likely diagnosis, the time to onset after exposure to the vaccine and alternative explanations for the diagnosis, and clustering by location (e.g., single clinic) [50]; inferring whether groups of ‘similar’ cases occur more commonly than expected within the SRS using both algorithmic and statistical methods [51,52]; and presenting this information to the expert reviewer in an intuitively appealing manner. While currently identifying similar cases relies primarily on application of case definitions by medical experts, advances informahealthcare.com
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in informatics might allow for automation of some or all of this work. Improvements in statistical methods of inference from SRSs are also needed. Mining social media, user-generated internet data & mobile communications
The mining of social media for public health information has received attention recently because of the success of ‘Google flu trends’ [53] in identifying influenza transmission and the identification of drug–drug interactions from patient-generated internet data [54,55]. Vaccine safety issues are discussed on internet blogs and Twitter but most such discussions lack the necessary details typically used for case series evaluations. Whether aggregating the information would allow those who monitor vaccine safety to take advantage of the ‘wisdom of the crowd’ remains to be fully evaluated [56]. Key issues in this evaluation are whether such approaches might provide earlier warning of emerging safety concerns or identify geographically localized clusters for regulators and public health authorities. Such approaches might be useful in settings where no or weak SRS are present or to reduce the cost of vaccine safety surveillance, but these hypotheses remain to be demonstrated. Traditional SRSs are resource intensive but there might be an opportunity to use mobile phones to allow health professionals to inexpensively send an alert to a central monitoring point regarding adverse events [57]. The collation, investigation and analysis of such reports remain a challenge, but might be facilitated by both new analytic strategies and the development of regional networks. Population-based system infrastructure & methods development
The continued expansion and refinement of the infrastructure allowing for evaluation of vaccine safety concerns in large populations are likely to continue. The adoption of electronic medical records on a wide scale should lead to improvements in the efficiency and quality of data available for assessments. But improvements in the backbone electronic health data systems alone will not be sufficient as they will need to be linked to vaccination and other registries that contain data not available in the core systems. These improvements should allow better assessments of vaccine safety in pregnancy and other special populations. While large countries and political entities like the USA, the EU and China will likely have sufficient resources and populations to build stand-alone systems, it will be important for smaller countries to build regional networks and to have a comprehensive description of vaccine distribution to facilitate sharing of vaccine safety information across countries and regions. The continued development and improvement of methods for vaccine safety surveillance are another area of growth. The last decade has seen the expanded use of a variety of selfcontrolled and near real-time methods for safety studies and surveillance. Assessment of potential bias in observational data, signal detection in population-based systems and quantitative 459
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benefit–risk analysis are areas likely to see real improvements. Worth noting is the work conducted by the Observational Medical Outcomes Partnership in applying the concept of evidence-based epidemiology to pharmacoepidemiological methods for drug safety [58], but the implications of this work for vaccine safety surveillance have not yet been explored. Because of this greater reliance on observational data and epidemiological assessment in both drug and vaccine safety assessment, there is likely to be a convergence of vaccine safety, drug safety and product quality surveillance systems [59]. These systems will come to rely on the same informatics and communication backbone and use similar analytic strategies, still informed by the experts in the particular disciplines. This might result in efficiencies and linkages that were heretofore unobtainable. One might even envision a system in which aggregation of large numbers of ‘tweets’ with only the minimal data elements previously described provide an early alert which is assessed using higher quality reports from SRSs and data about product and lot quality, while sufficient data accumulate in population-based systems for rigorous evaluations to be conducted. Pathogenesis of vaccine AEs & personalized vaccination
The pathogenesis of many adverse events will likely become better understood and linked to specific genetic profiles as a result of major investments in understanding disease pathogenesis in general and vaccination in particular. Personalized vaccination will become theoretically possible as the cost of generating genetic profiles is reduced. This will lead to major challenges to the current paradigm of population-based vaccination and new approaches to vaccine safety focused on either vaccine modification or individual exclusions based on genetic profiles might be needed. Recognizing the complexity of this undertaking, two major initiatives have been started. In Europe, the Innovative Medicines Initiative has launched project BioVaxSafe, and in the USA, the National Institutes of Allergy
and Infectious Diseases has launched several major initiatives to better understand the immune response to vaccination including adjuvants. While there has been growing interest in utilizing genomic information to predict safety and efficacy in clinical trials, most serious adverse effects caused by vaccines are rare and currently can only be studied in the postmarketing period after large numbers of people are vaccinated. Identifying and understanding host factors that predispose to these adverse effects could help to clarify whether they are a result of a genetic predisposition. Creation of a repository of tissue specimens from people who have experienced adverse effects after vaccination has been proposed as a means of making the process of studying genomic risk factors more efficient, but has proven difficult. Building such a repository would constitute an important step toward comprehensive understanding and helping to prevent these adverse effects. Future ‘personalization’ of vaccine safety is largely contingent on advances in genomic science generally, especially the ability to inexpensively provide individuals with their genetic sequence. Ultimately, this knowledge may help to maintain the public’s confidence in vaccines, provide more complete evidence for rational vaccination polices, guide development of safer vaccines and further protect public health. Financial & competing interests disclosure
This article reflects the views of the author and should not be construed to represent FDA’s views or policies. This work was supported as part of the author’s duties as an employee of the US FDA. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Vaccination will be more important than ever as a disease prevention strategy as more vaccines are introduced and more people are vaccinated globally. • Vaccination is very safe but rare adverse effects do occur. • Declining vaccine-preventable disease incidence leads to increased public demands for evidence of vaccine safety. • Pathogenesis of many adverse events will become better understood and linked to specific genetic profiles aided by the collection of tissue samples in adverse event biorepositories. • Personalized vaccination will become theoretically possible as the cost of generating genetic profiles is reduced. • Postmarketing surveillance coupled with epidemiological studies are necessary to monitor vaccine safety in actual use and improvements in methods will continue. • New technologies, especially informatics, internet and mobile communications, will be evaluated and integrated into vaccines safety surveillance system. • Convergence of vaccine safety, drug safety and product quality surveillance systems will increase. • Vaccines will become even safer and vaccination will thrive as a disease prevention strategy.
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Perspectives on the future of postmarket vaccine safety surveillance & evaluation
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