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Priorities for the National Vaccine Plan 1 Development of New and Improved Vaccines Vaccines are complex products and the science of vaccinology is difficult. To achieve the full promise of modern science and technology to prevent and treat disease by immunization, America’s cooperative and collaborative relationships in vaccine research and development are interwoven into a fabric of innovation. This must be maintained and strengthened. It is important to understand the nature of these relationships to prevent inadvertent damage to this delicate fabric. (NVAC, 1997) In 1997, the National Vaccine Advisory Committee (NVAC) authored an article in the journal Pediatrics titled “United States Vaccine Research: A Delicate Fabric of Public and Private Collaboration,” which provided a synopsis of the complexity and fragility of the U.S. vaccine enterprise at that time. The committee is not aware of an update of the 1997 article, but a contemporary overview would reflect a number of great advances and some areas in which considerable challenges in the efficient use of vaccines to prevent infectious diseases persist, including scientific hurdles and periodic shortages in vaccine supply (also discussed in Chapter 4) (Goldberg et al., 2002). In this chapter, the committee briefly describes vaccine research and development and major themes that emerged at a meeting with stakeholders about this goal in the draft National Vaccine Plan. Based on those themes, a review of the objectives and strategies in the draft plan, and a review of the pertinent literature, the committee discusses gaps and opportunities in vaccine development and makes several recommendations on priority actions in Goal 1 of the draft plan, and a policy recommendation pertaining to the scope of the plan.
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Priorities for the National Vaccine Plan CONTEXT: THE CURRENT STATE OF VACCINE RESEARCH AND DEVELOPMENT Although Goal 1 of the draft National Vaccine Plan is not titled “vaccine development and regulation,” the two processes are profoundly intertwined; the outcome of successful vaccine development is licensure by the Food and Drug Administration (FDA) of safe and effective vaccines that will improve the public’s health. Infectious disease vaccine development and regulation occur in a dynamic environment shaped by public health considerations and policies, scientific and technologic barriers, news media commentary, judicial decisions, and the multiple public avenues available for information exchange. A major challenge to the field is meeting the necessarily very high standard of safety for preventive vaccines used in healthy populations. Also, vaccines are generally used for large proportions of the population, for example, childhood vaccines for an entire birth cohort (e.g., 4 million newborns annually in the United States alone), and in hundreds of millions of people worldwide. The pharmaceutical companies that produce vaccines “experienced a period of great contraction in the 1980s and 1990s”1 (reasons that have been described include fear of liability, low profit margins, and low likelihood of recouping investment), but the first decade of the 21st century appears increasingly promising for the industry, as demonstrated by expansion in the number of manufacturers, a promising pipeline of potential new vaccines, and a changing view of the profitability of vaccines (Werble, 2009a,b). The industry conducts most of the applied and clinical research necessary for the further development and production of a vaccine. The federal government supports vaccine research through several agencies including the National Institutes of Health (NIH) in the Department of Health and Human Services (HHS) and the more recently established Biomedical Advanced Research and Development Authority (BARDA), located in the office of the Assistant Secretary for Preparedness and Response (ASPR) also in HHS.2 NIH funds basic and clinical vaccine research totaling an estimated $1.675 billion in 2009. The majority of vaccine-related research at NIH takes place in the National Institute of Allergies and Infectious Diseases (NIAID). NIH and BARDA also represent two different and complementary approaches to vaccine development. NIH has long supported primarily an 1 In 1967, 26 vaccine manufacturers were licensed by FDA, while in 2002, only 12 FDA-licensed vaccine manufacturers remained (Plotkin et al., 2008). According to the 2004 IOM report Financing Vaccines in the 21st Century, five companies made all vaccines routinely recommended for children and adults, and two were based in the United States—Merck and Wyeth (recently purchased by Pfizer, a U.S. pharmaceutical company), and the others were Europe-based multinationals. 2 ASPR was created in 2006 by the Pandemic and All-Hazards Preparedness Act.
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Priorities for the National Vaccine Plan investigator-initiated approach, which is generally open ended and not targeted, while BARDA has taken a product-driven approach3 to vaccine development. One example of BARDA’s approach may be found in its June 2009 award of $35 million to a company that is expected to develop “recombinant influenza vaccines based on hemagglutinin genes or proteins (plasmid DNA, virus-vectors, peptides, subunit proteins and virus-like particles) … leading towards FDA-licensure and human usage” (BARDA, 2009). The vaccine programs under BARDA also offer an example of the regulatory system’s potential for flexibility. Specifically, FDA’s promulgation of the so-called “animal rule”—regulations that describe the conditions under which efficacy data in animals may be submitted in lieu of data from human trials—has allowed BARDA and the companies it supports to evaluate the safety and efficacy of vaccines for biodefense for which human challenge with the pathogen would be unethical or unfeasible (Abdy et al., 2007; FDA, 2009d). (Clinical studies with humans are still needed to demonstrate a vaccine’s safety and immunogenicity.) Developing and manufacturing most4 vaccines involves using living organisms and presents unique technical and regulatory challenges. Vaccine manufacturers may need to build or renovate a manufacturing facility specifically for the production of a given vaccine before that vaccine has been licensed. This results in a “sunk cost”—a cost that cannot be recovered if the vaccine is not licensed (Coleman et al., 2005). As part of the Biologic License Application, FDA evaluates the manufacturing process and facility (Landry and Heilman, 2005). The vaccine regulatory process is also complex and difficult, requiring a high level of scientific expertise and sustained funding for its maintenance and enhancement. FDA’s role in recent years has been shaped by two major events. In 2004, the agency announced its Critical Path Initiative, which is intended to bring about an infusion of scientific innovation into its work and spur the same in the companies that develop drugs, vaccines and other biologic products, and devices, with the ultimate goal of translating innovation into safe and effective products (FDA, 2004). FDA’s effort to “modernize the scientific process” that transforms a discovery or proof of concept into a vaccine continues, and the agency publishes yearly compendia of activities it has undertaken or supports, in an effort to bring about the desired changes 3 Requirements for BARDA’s Project Bioshield include “solid clinical experience and/or research data” that support “a reasonable conclusion that the countermeasure will qualify for [FDA] approval or licensure within eight years after the date of a determination” (Hynes, 2007). The term “countermeasure” refers to vaccines, drugs, and other medical products intended to prevent or treat effects of bioterrorism. 4 Newer synthetic sub-unit vaccines are an exception.
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Priorities for the National Vaccine Plan (as an example, see Oliva et al., 2007).5 In 2007, the FDA Amendments Act called for several changes that signal an even greater emphasis on science at FDA and are expected to lead to increased financial and human resources for the agency.6 THEMES FROM INFORMATION GATHERING The committee gathered input from stakeholders and compared it to the objectives and strategies in Goal 1 of the draft plan; reviewed pertinent literature; and developed a series of themes indicating potential opportunities for improvement in vaccine development. These themes include (1) the role of the regulatory system; (2) the need for a priority-setting approach to vaccine research and development; (3) the need for coordination of research in vaccine development; and (4) the potential desirability of expanding the scope of the National Vaccine Plan to transcend the 1986 definition of vaccines as limited to prevention of infectious disease vaccines. REGULATORY ENHANCEMENTS TO SUPPORT INNOVATION WHILE PROTECTING HEALTH One topic not addressed by the existing Goal 1 objectives is the regulatory system that licenses vaccines and has the potential to facilitate or inhibit innovation.7 The importance of addressing regulatory issues in the National Vaccine Plan was discussed at the committee’s meeting with stakeholders on Goal 1 in the plan, and NVAC and the National Vaccine Program Office (NVPO) have received input from stakeholders on the subject of the interaction between regulators and companies seeking licensure of new vaccines (IOM, 2008; NVPO, 2009). Despite some important scientific and technologic advances, change has been slow to occur in some areas of vaccine development. For example, an observation made by William Jordan and his colleagues at NIAID in the 1970s continues to be relevant today. They found that vaccine 5 Recent examples of FDA-conducted research include development and evaluation of animal models needed to characterize the immune response to bacterial pathogens such as anthrax and pertussis and development of biomarkers indicating vaccine efficacy; development of assays to evaluate protection conferred by pneumococcal vaccine; and study of the antibody response against polysaccharide in the coat of bacterial pathogens such as pneumococcus and of the immunomodulatory effects of specific polysaccharides (FDA, 2009c). 6 These include the creation of the position of Chief Science Officer and increased funding from fees manufacturers pay at major points during the regulatory application process. 7 As an example, FDA’s Critical Path Initiative was launched in 2004 “to create a framework for stimulating efforts to modernize the development, evaluation, manufacture and use of medical therapies and other FDA-regulated products” (FDA, 2009b).
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Priorities for the National Vaccine Plan … development was hindered by the lack of investment to obtain a missing piece of scientific knowledge or technology. Just as the new molecular biotechnology was becoming available, there was an awareness of a lack of coordinated planning and funding to assure that each step in vaccine development followed as rapidly as possible the preceding one. Although the United States can point to major triumphs in vaccine development in the past 20 years, these old problems have not been eliminated. (HHS et al., 2002) The Jordan Report: Accelerated Development of Vaccines 2007, a compendium of expert articles published by NIAID, noted that NVAC “called for review of existing cGMP [current Good Manufacturing Practices] requirements to assure they are science-based, potentially eliminate or modify those that are not, and allow for flexibility as long as it does not compromise the safety and efficacy of the vaccines” (HHS et al., 2007:22). It seems, based on stakeholder input that the committee received, that greater progress toward regulatory efficiency and flexibility (while preserving a focus on safety and efficacy) remains a concern (IOM, 2008). The great, overarching challenge in bringing new and improved vaccines to market is that new vaccine development and regulation are closely linked processes that tend to be risk-averse.8 Although there are examples of both industry innovation and agile, flexible regulatory approaches, including development of vaccines supported by BARDA and recent development of pandemic influenza vaccines, a considerable proportion of vaccine production and regulation is shaped by an old paradigm of what vaccines are and how they should be studied and regulated. For various reasons, the regulatory process more easily tips toward the tried and true rather than toward innovation (Klein and Myers, 2006). Adjuvants are substances added to vaccines to enhance the immune response (FDA, 2009a), and they represent one of the new frontiers in vaccine development because of their potential effects ranging from strengthening immune response in some individuals (e.g., older adults) to achieving efficacy with smaller amounts of antigen. The challenges of testing and licensing vaccines containing promising new adjuvants have delayed consideration of those adjuvants by U.S. vaccine companies and regulators (Aguilar and Rodríguez, 2007). Also regulators continue to rely on classic randomized controlled trials despite the fact that they leave many unanswered questions about how a vaccine will work in real-life use (Poland et al., 2009). Finally, some newer vaccines to prevent diseases for which a vaccine already exists are simply reformulations or combinations of existing vaccines, which seems to suggest the existence of barriers to true innovation (Brennan and Dougan, 2005). 8 These may include risk of failure for company, sunk costs that present a high threshold for entry into the vaccine market, and regulatory aversion to risk.
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Priorities for the National Vaccine Plan Several vaccines containing new adjuvants have been developed, and some are licensed for use in Europe,9 but until October 2009, aluminum-containing compounds were the only adjuvant used in some FDA-licensed vaccines. (Cervarix, GlaxoSmithKline’s [GSK’s] newly approved HPV [human papillomavirus] vaccine contains the adjuvant ASO4 that combines aluminum hydroxide with monophosphoryl lipid A.) Although aluminum-containing adjuvants have been in use for 80 years, Aguilar and Rodríguez (2007) assert that were they newly discovered today, their side effects and toxicity could make them difficult to license by contemporary standards. Both FDA and the vaccine industry recognize the scientific challenges of evaluating new adjuvants, and FDA has begun to make progress with strategies to enable evaluation and licensure of adjuvants with favorable risk-benefit profiles. In 2008, an NVAC subcommittee report on dose optimization strategies suggested assuring that “FDA guidance on approaches to licensure path for novel adjuvant systems from regulatory agencies receives high priority in the Critical Path Initiative, with funding support as necessary, for expeditious publication” (Dekker et al., 2008:12). In its 2008 summary of Critical Path Initiative projects, FDA acknowledged “a severe shortage of analytical tools to evaluate new adjuvants,” and an ongoing FDA project is focused on developing methods for preclinical evaluation of novel adjuvants using in-vitro screening methods (FDA, 2009b). The summary from a June 2009 World Health Organization (WHO) consultation meeting to inform the WHO Global Advisory Committee on Vaccine Safety and the Strategic Advisory Group of Experts on Immunization stated that “[o]verall, no significant safety concern or barriers to evaluating or using adjuvanted vaccines for the current H1N1 vaccine were raised” (WHO, 2009). The European Medicines Agency (EMEA) has established a process that allows vaccine manufacturers to submit preliminary applications using a non-pandemic strain with adjuvant. Once manufacturers replaced the strain in the vaccine with the pandemic strain (beginning in July 2009), they could resubmit their application and be granted approval in as little as five days if the agency was “satisfied that the extrapolation to the new strain was valid,” but they would need to provide EMEA with new data after the vaccine begins to be used (Declan, 2009). An August 2009 FDA presentation described one of the objectives of clinical evaluation of H1N1 vaccines as “evaluat[ing] investigational adjuvants to provide data on their utility in dose sparing and enhanced immunogenicity” (Baylor, 2009). It is probably too early to tell whether adjuvants will be called for or to predict the direction of FDA’s regulatory decisions regarding adjuvants for pandemic influenza vaccines. Randomized controlled trials have been the gold standard in the regu- 9 For example, the European Medicines Agency licensed an HPV vaccine adjuvanted with ASO4 in September 2007 and an H5N1 pandemic influenza vaccine adjuvanted with AS03 in September 2009.
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Priorities for the National Vaccine Plan latory process leading to the approval of vaccines (Poland et al., 2009). However, randomized controlled trials have limitations. For example, they may not represent results achieved with the actual use of vaccines—results obtained in healthy subjects typically enrolled in such trials may not be informative about the vaccine’s safety and efficacy in populations that are heterogeneous with respect to age, health status, and genetics. Several stakeholders at the committee’s meeting on Goal 2 in the draft plan (vaccine safety) mentioned related concerns, such as the fact that vaccines for pediatric use are studied in healthy children, who may not be representative of children with chronic and serious illnesses or other subgroups. Alternatives could include using randomized controlled trials to prove efficacy, evaluating surrogate markers, then evaluating surrogate markers in selected populations and/or conducting Phase IV (post-licensure studies) in such populations. Some have argued that regulatory authorities are excessively risk averse, even when the risk is merely theoretical. Plotkin (2005b), for example, wrote that the 2003-2004 influenza vaccine was not adequately matched to the influenza strains circulating that season due to regulatory reluctance to allow use of a cell line that posed a “hypothetical” risk. Such occurrences are not only a regulatory and administrative matter, but may also negatively affect the public perceptions of the effectiveness of influenza vaccine in general. Some of the regulatory barriers to vaccine development are not related to problems of vaccine quality, safety, or efficacy. Rather, they appear to be linked to organizational and policy matters, and may reflect bureaucratic obstacles rather than scientific processes and priorities (Miller and Henderson, 2007; Poland et al., 2009). Some regulatory barriers may relate to communication challenges between manufacturers and regulators (including FDA, the Office of Human Research Protections), misunderstandings, or procedural requirements that may be tangential to a study (Coleman et al., 2005; Glezen, 2006). Industry respondents to a qualitative study (of four pharmaceutical companies) found communication with European regulators much more “open” than with their American counterparts and this point has been echoed by others, including stakeholders informing this IOM committee at its December 2008 meeting (Coleman et al., 2005; IOM, 2008). One industry analyst wrote that “new technologies often languish because there’s nobody inside FDA with sufficient time or resources to help them clear key scientific hurdles on the way to proving they are safe and effective” (Gottlieb, 2004). There is an unmet need to translate the best of current science and technical innovation into the regulation of safe and effective vaccines. Although this is part of the mission of FDA’s Critical Path Initiative, the 2009 budget for the initiative was only $5 million. The 2007 FDA Amendments Act also called for the establishment of the Reagan-Udall Foundation to
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Priorities for the National Vaccine Plan “modernize … product development, accelerate innovation, and enhance product safety,” but the foundation’s efforts to advance regulatory science has been delayed by congressional concerns about conflicts of interest on its board (Nature Reviews Drug Discovery, 2008). A systematic approach could be used to assess and validate new technology that might replace older, time-consuming approaches currently used to ensure safety. One example relates to the testing of vaccines for the possible presence of adventitious infectious agents. It has been suggested that instead of using conventional culture methods, rapid and highly sensitive modern methods (some may already be in use in some cases) such as polymerase chain reaction and automated DNA sequencing could be used to detect such agents more quickly (Glezen, 2006). Another area in which improvement is possible is the use of bioassays used for testing vaccines. The animal tests used to assess the safety of older vaccines, such as whole cell pertussis vaccine (still used in the developing world) are decades old, and according to Milstien (2004) are neither precise nor predictive of a vaccine’s safety in humans but continue to be required by some regulatory agencies.10 Some animal tests, such as the abnormal toxicity test,11 which remains in use in the United States but has been eliminated by most European regulatory agencies, are of questionable utility (Feigelstock, 2008; Milstien, 2004). Because the topic of vaccine research and development is linked with issues in the goals pertaining to vaccine safety and vaccine use, several themes emerged from meetings of the committee with expert stakeholders on those goals in the draft National Vaccine Plan. Some stakeholders urged that the drafters of the National Vaccine Plan consider the need for improvements in information sharing among manufacturers, academe, and government, by addressing antitrust and intellectual property or proprietary considerations that are barriers to vaccine development and production. For example, industry scientists do not share failures that occur at the level of basic science and discovery, leaving others to unknowingly attempt the same or similar processes. Others called for facilitating the licensure of process improvements, novel delivery systems, and adjuvants. There were also discussions at two of the committee’s meetings that focused on the importance of differentiating among the populations that may be given a vaccine. That is, the risk-benefit considerations for licensing products targeting certain populations at high risk from a vaccine-preventable disease (e.g., older adults, people with chronic conditions such as those on renal dialysis) may be different from those for vaccines intended for use in healthier populations. An additional theme pertained to furthering efforts to achieve international harmonization of regulatory requirements (e.g., to facilitate more rapid licensure in Europe 10 See, for example, Kataoka et al., 2009, and Thalen et al., 2008. 11 Product is injected into two guinea-pigs and five mice that are observed for 7 days (Milstien, 2004).
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Priorities for the National Vaccine Plan of a vaccine approved in the United States and vice versa) to accelerate the development and introduction for global use of new and improved vaccines and to reduce the cost of vaccine development. Based on input from stakeholders, a review of pertinent literature, and its own deliberations, the committee found that there are aspects of vaccine development and regulation that can impede innovation without improving safety, efficacy, or immunogenicity, although recent changes at FDA suggest that the regulatory environment is strengthening its scientific foundations. Recommendation 1-1: The National Vaccine Plan should incorporate improvements in the vaccine regulatory process that reflect current science and encourage innovation without compromising efficacy and safety. Improvements include the following: Strengthening communication with vaccine developers through more frequent workshops and guidance documents, and Revising procedures and standards for developing, licensing, and producing vaccines for infectious diseases that encourage flexibility and innovation. To ensure that FDA can play an optimal role in vaccine development, its Center for Biologics Evaluation and Research must have funding and staffing commensurate with its responsibilities to identify, develop, and apply the best and most current regulatory science to review of vaccine products. PRIORITY SETTING IN VACCINE RESEARCH AND DEVELOPMENT A second theme identified by the committee that is congruent with Objective 1.1 in the draft plan emphasizes the importance of developing and periodically updating a prioritized list of needed new and improved vaccines. Several industry stakeholders and academic researchers at the December 2008 meeting stated that if the government described the priority diseases for which vaccines are needed and any critical specifications for those vaccines, companies would be eager to deliver them. Previously, a 2003 NVAC report found that a unified approach to federal prioritization of vaccine development, so as to assure that public health needs are met, is an important component of vaccine development. An approach suggested in the 2003 report was for NVPO and NVAC to provide a mechanism for
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Priorities for the National Vaccine Plan a unified federal prioritization of vaccine development and distribution as specified in the 1986 enabling legislation.12 In 1985, IOM released two related reports titled New Vaccine Development: Establishing Priorities Volume 1, Diseases of Importance in the United States and Volume 2, Diseases of Importance in Developing Countries (IOM, 1985a,b). The committee that authored these reports developed a quantitative model that could be used by decision makers to prioritize the development of vaccines against a number of infectious diseases considered significant threats to public health. Several of the candidate vaccines considered in that report have been licensed since its publication and are now in use, including recombinant hepatitis B virus, hepatitis A virus, varicella zoster virus, Haemophilus influenzae b (Hib), rotavirus, and acellular pertussis vaccine. The other candidate vaccines remain at various points in the pipeline. More than a decade later, NIH requested that IOM convene a new committee to assess the progress made since publication of the 1985 reports, to “discuss important barriers to vaccine research and development, and develop another quantitative framework for prioritizing vaccine development” (IOM, 2000). That committee selected 26 candidate vaccines and analyzed them using an “annualized value of the costs per quality-adjusted life year gained by a vaccine strategy.” The candidate vaccines were then placed into four quartiles reflecting the extent to which a vaccination strategy would save money (I—most favorable, II—more favorable, III—favorable, IV—less favorable). The resulting report discussed how insufficient interest on the part of funders, such as private vaccine companies conducting research and development, can reflect concerns about profitability because of either poor market potential or possible costs due to liability for adverse events. “Stable and sufficient funding of basic research by the federal government, the use of creative funding mechanisms, and the creation of alliances between the public and private sectors are crucial to ensuring that effective, safe, and needed vaccines will be carried through the development stage into licensure” (IOM, 2000:124). A comparison of the 2000 IOM report to the update on vaccine development and research in the 2007 Jordan report (HHS et al., 2007) shows that of the three kinds of vaccines ranked in the first quartile (most favorable) based on strength of the evidence (cytomegalovirus, universal influenza, streptococcus pneumonia), none has been developed, and of the seven kinds of vaccines ranked in the second quartile (more favorable), only vaccines against HPV and tuberculosis have been developed and have received FDA approval. The process of prioritization of candidate new vaccines also needs to 12 The National Childhood Vaccine Injury Act.
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Priorities for the National Vaccine Plan include the Centers for Disease Control and Prevention (CDC). Landry and Heilman (2005) wrote that by engaging in early and wide-ranging discussions with companies, the advisory committees and the CDC staff can review broad criteria concerning future needs for and address what-if scenarios regarding candidate vaccines—e.g., if a respiratory syncytial virus vaccine had these characteristics, would it be considered for use in high-risk infants only or all newborns? The companies can often review early directions in research and development with the advisory bodies, although confidentiality because of the competitive forces of the marketplace will sometimes limit such discussions. Similarly, Plotkin (2005b) has commented on the potential role of the Advisory Committee on Immunization Practices (ACIP) in a dialogue about setting vaccine development priorities: Public health authorities need to indicate which vaccines would be used if they were developed. The recent Institute of Medicine (IOM) report on priorities for vaccines is a signal example of what can be done, but to my knowledge it has never been discussed by the ACIP, nor has the ACIP indicated which of the priorities given by the IOM it agrees with. The 2000 IOM report identified major gaps in data and research relevant to some infectious diseases of public health importance (e.g., Treponema pallidum, Clostridium perfringens, enterococci) and found that “research in fields such as epidemiology, health services research, health economics, human behavior, and even ecology” could help to advance vaccine development and program implementation. However, the committee that authored the 2000 report was surprised by a “lack of data and research in these fields, information that would have been useful to the committee in assessing disease burden” and “[i]n some cases, no significant new data had been published since that referenced in the 1985 IOM report on vaccine priorities, particularly national data on disease characteristics such as morbidity states and patterns of care” (IOM, 2000:124). The experience of the committee that authored the 2000 report may help to illustrate how a systematic, national process of priority setting could help identify areas in which research is needed and perhaps spur such research. For example, encouraging new targeted burden of disease studies, rather than repeating prioritization exercises using existing data, would further knowledge in the field and provide a more up-to-date basis for decision making. Development of an HIV vaccine remains a critical priority for HHS and all stakeholders; the committee was surprised that the new draft plan did not mention an HIV vaccine. Another example of a currently unmet need that was mentioned at two or more stakeholder meetings is the emergence of difficult-to-treat bacterial infections, such as methicillin-resistant Staphylococcus aureus and Clostridium difficile, as increasingly worrisome public
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Priorities for the National Vaccine Plan health problems that potentially could be addressed through the development of effective vaccines. As noted above, the draft National Vaccine Plan includes identifying vaccine research and development priorities as an objective in Goal 1, but does not call for a formal, systematic process for priority setting. It was suggested at the February 2009 NVAC meeting that the plan elaborate on vaccine priorities for the United States and the products needed to address the lack of a systematic approach to vaccine development. An industry representative commented that from a commercial perspective, concerns remain about how—or whether—to develop vaccines for small or uncertain markets (NVAC, 2009). This sentiment—that it would be desirable and helpful if a government entity could identify which products should move forward—was also expressed repeatedly by stakeholders at this IOM committee’s meeting on research and development. Although the committee recognizes that companies include additional factors, such as commercial potential, in their decision making, the committee has observed a level of agreement on the need for guidance toward a unified list of priority vaccines. The committee found that there currently is no ongoing, evidence-based process involving all relevant stakeholders by which candidates are identified as priorities for vaccine development in industry and government programs. Such a process could accelerate the development of vaccines by identifying both the need and the likely market—linking priorities (vaccines with certain specified characteristics) to ACIP recommendations for use. The committee concurs with the draft plan’s attention to prioritization of candidate vaccines and offers the following recommendation. Recommendation 1-2: The National Vaccine Plan should incorporate the development of an evidence-based approach for prioritizing new and improved vaccine candidates by targeted disease and develop specifications for high-priority vaccines to accelerate their development.13 Such an approach would ideally involve government agencies and all relevant stakeholders and take place under the aegis of NVAC or a similar entity. The approach to priority setting may have some of the following attributes: Supporting disease burden studies (e.g., morbidity and mortality) when needed for vaccine prioritization; 13 This recommendation refers to development of vaccines as defined by the 1986 act—vaccines to prevent infectious diseases.
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Priorities for the National Vaccine Plan Employing outcome measures that capture both survival gains and quality-of-life improvements;14 Use of cost-effectiveness analysis; and Consideration of the technical and scientific feasibility of vaccine development as a prioritization criterion. A process for priority setting would be strengthened by incorporating evidence or guidance available from previously published work linking research and funding levels to national priorities.15 Two parallel but separate processes are needed to prioritize vaccine targets for U.S. and global use, reviewing two different sets of burden of disease data, cost-effectiveness data, and other information. The committee recognizes that although quantitative ranking systems can inform, they are only one source of information in making policy decisions. COORDINATION AND OVERSIGHT OF VACCINE DEVELOPMENT A great deal of remarkably productive vaccine-related research takes place in the United States. However, the majority of NIH-supported research is comprised of investigator-initiated studies (NIH, 2009a,b). Such an approach is responsible for discoveries that may lead to new vaccines and, in the case of difficult scientific challenges (e.g., developing an HIV vaccine) may be necessary. On the other hand, proceeding from a list of priority vaccines to the development of those vaccines would benefit from a more planned and coordinated approach. For example, BARDA requests for proposals include detailed specifications for the vaccines needed (HHS, 2009).16 A high level of coordination among stakeholders and pertinent government agencies would be beneficial in the development and licensure of vaccines identified in the process of prioritization described on preceding pages. Based on comments received at its December 2008 meeting on developing new and improved vaccines and on a review of relevant literature, the committee understands that barriers to coordination remain, although interactive dialogue has, indeed, been fostered among the relevant federal agencies, advisory committees, and industry. 14 Quality-adjusted life years, or QALYs, have been suggested for use in the United States for priority setting in vaccine development (IOM, 2000). Disability-adjusted life years, or DALYs, have been suggested for use internationally. However, it is important to note that both measures have their proponents and critics, and that there are other measures of health outcome that could be used to inform a process of priority setting. 15 See, for example, Gross et al., 1999, and Neumann et al., 2005. 16 BARDA issued a request for proposals (RFP) in 2007 for advanced development of recombinant influenza vaccines based on hemagglutinin genes or proteins that may be manufactured in 12 weeks or less after the beginning of a pandemic with the goal of awarding contract(s) toward FDA licensure (HHS, 2009).
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Priorities for the National Vaccine Plan The 2009 H1N1 vaccine development effort provides an example of the potential of public-private coordination. Shortly after the recognition of the novel H1N1 outbreak, CDC prepared a vaccine seed strain and shared it with manufacturers. In April 2009 the acting CDC director stated that “HHS has also identified the needed pathways to provide rapid production of vaccine after the appropriate seed strain has been provided to manufacturers” and that as vaccine development progressed, “HHS operating divisions and offices including CDC, NIH, FDA, and ASPR/BARDA [would] work in close partnership” (Besser, 2009). The committee found that the vast majority of NIH-supported peer-reviewed vaccine research is investigator-initiated and that coordination among federal agencies and with academic and private sector stakeholders could be strengthened. Furthermore, some examples of innovative and productive intersectoral collaboration come from the development of vaccines for global health, such as the approach of public-private product development partnerships (PDPs). Public-private partnerships such as PDPs have a long history both in the United States and in other countries. One example dates back to the World War II era collaboration among government, academia, and industry to develop the first licensed vaccines against influenza and pneumococcal pneumonia, improved vaccines against smallpox and tetanus, and other new or improved vaccines (Hoyt, 2006). Contemporary PDPs are involved in efforts to accelerate the development of an AIDS vaccine (e.g., the International AIDS Vaccine Initiative, IAVI) and vaccines for malaria and tuberculosis (TB) (e.g., the Malaria Vaccine Initiative, the Aeras Global TB Vaccine Foundation). (Chapter 5 provides additional discussion.) Recommendation 1-3: The National Vaccine Plan should incorporate creation of a strategy for accelerating development of high-priority vaccines17 that (a) engages all relevant institutes within NIH and the Department of Defense, academic investigators, and private sector partners; and (b) adapts lessons learned from innovative past and present public-private partnerships. This coordinated, outcome-focused approach to vaccine development would be periodically reassessed to ensure appropriateness. The strategy for accelerating vaccine development may be two-part: (1) high-level, cross-cutting needs for innovation in manufacturing processes and other aspects of technology, and (2) needs for new vaccines against specific diseases or new combination vaccines. The drafters of the plan could explore what 17 Per Recommendation 1-2.
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Priorities for the National Vaccine Plan combinations of government agencies and stakeholders could best address these connected areas. The very slow shift from egg- to cell-based production of influenza vaccine further illustrates the need not only for high-level prioritization of vaccine research, but also for strong government support of coordination to achieve those priorities. Hens’ eggs have been used to grow influenza virus to make influenza vaccine for decades, although development of a cell-based vaccine has long been recognized as the way forward to improve vaccine production capacity. Despite the technical feasibility of producing a cell-based influenza vaccine, the shift from eggs to cells requires a substantial investment in licensing a new process that is costly, complex, and risky. The change also requires addressing scientific and regulatory questions about the safety, reactogenicity, immunogenicity of cell-based vaccine, while continuing to produce egg-based vaccine entails comparatively fewer financial or opportunity costs (although the availability of hens’ eggs has been a limiting factor in recent years). The global concern about the potential of pandemic influenza and the concomitant need to facilitate rapid, large-volume production of influenza vaccine was one of the incentives for exploring different approaches to its manufacturing. THE MEANING OF “VACCINE” IN THE 21ST CENTURY The committee believes that the scope of the National Vaccine Plan could be broadened to include classes of vaccines other than vaccines intended to prevent infectious diseases. Such an expansion would recognize the fact that vaccines against infectious diseases are already benefiting from research and development efforts on other vaccine or vaccine-like entities, and that common immunologic platforms may be useful for different types of vaccines. The language of the 1986 act is a clear reflection of its time. The purpose of the program described in section 2101 of the act is “to achieve optimal prevention of human infectious diseases through immunization and to achieve optimal prevention against adverse reactions to vaccines.” In 1986, immunization and vaccines were quite firmly linked to or identified with infectious disease, and there was limited recognition of vaccines’ potential role as therapeutic modalities or as preventive against cancer or other chronic conditions. The 1985 IOM report recommended a list of priority vaccines that included only vaccines against infectious disease agents. Fifteen years later, the IOM report Vaccines for the 21st Century (2000) reflected the broader understanding of vaccines and immunization and proposed a list of priority vaccines that included several therapeutic vaccines (e.g., for insulin-dependent diabetes mellitus, multiple sclerosis, and rheumatoid arthritis). Since 1986, vaccines have been licensed that help prevent hepatitis B and
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Priorities for the National Vaccine Plan human papilloma viruses that may cause cancers of the liver and cervix, respectively. As Plotkin (2005a) wrote, Active immunization has heretofore been largely confined to infectious diseases, with some use of desensitization to treat allergies. Now consideration is being given to immunization against a wide variety of noninfectious diseases. Most effort is being directed against cancers, in which novel cellular antigens are often present. Expanding the interpretation of vaccines and immunization in the statute would acknowledge the reality that the current vaccine landscape is broader than infectious disease vaccines; recognize the relevance of research advancing therapeutic and other non-traditional vaccines to the broader vaccine enterprise; and perhaps proactively position the federal government to support coordination and encourage wider utilization of what is learned in the entire field of vaccines. The committee acknowledges that developing a national vaccine plan is challenging and that a much broader scope would result if other types of vaccines were included under the plan’s purview. However, the plan’s statutory underpinnings imply a distinction between the “traditional” vaccines intended for prophylaxis against infectious disease and other types of vaccines (therapeutic, prophylactic against chronic disease) that is no longer useful. Coordination in this area may help to maximize the benefits of scientific discoveries, clarify regulatory expectations, and enable early consideration of the health care implications of new classes of vaccines. The committee does not believe that there is a federal government agency that currently oversees or coordinates work on other types of vaccines. Recommendation 1-4: Future iterations of the National Vaccine Plan should include classes of vaccines (such as therapeutic vaccines and vaccines against non-infectious diseases) beyond those expressly enumerated in the statute, and that the Secretary of HHS explore how best to assign responsibility for coordination in this area. The development, use, and evaluation of vaccines that depart from the traditional paradigm of preventing infectious disease could be strengthened if such vaccines were part of a broader national strategy. The broader view of vaccines described above would recognize the potential value of new vaccines beyond the “traditional” role of preventing infectious diseases, and proactively position the federal government to support coordination on and encourage the broader application of scientific and technologic breakthroughs related to non-traditional vaccines.
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Priorities for the National Vaccine Plan GLOBAL VACCINES Goal 5 in the draft plan calls for increasing “global prevention of death and disease through safe and effective vaccination.” The goal and the objectives within it, together with an added explanation,18 make it clear that research and development pertaining to vaccines for developing countries is included in Goal 1. Although, as the draft plan notes, scientific and technological approaches to developing vaccines for the developed and developing country markets do not differ, the ability to recoup investments and the existence of a viable market are strong determinants of manufacturer decision making about strains or serotypes of a microorganism that will be included in a given vaccine, and of the willingness to pursue development of vaccines for certain neglected diseases that affect large populations in low-income nations. Multinational firms have a strong incentive to move away from traditional vaccines that promise little or modest return on investment, and to focus their efforts on novel, more profitable vaccines for rich countries. As a result, vaccine development specifically for low- and middle-income countries is critically dependent on innovative financing mechanisms and delivery mechanisms for eventually available vaccines (see Chapter 5). It is important that the National Vaccine Plan includes objectives and strategies attentive to this challenging area. There may be unique scientific challenges to developing vaccines for populations in some developing countries. For example, there is evidence that children in some geographic areas have a less robust response to oral polio vaccine, the first Hib conjugate vaccine, and some rotavirus vaccines (Poland et al., 2009). The problem of subgroup differences in immunogenicity (and similar examples) seems related to vaccine development for vulnerable populations (e.g., strategies 1.2.2, 1.4.7, or 1.4.8 in the draft plan),19 but it is important that the plan make specific reference to these 18 “Given the breadth of global immunization activities, some of the Objectives and Strategies relevant to this topic are included elsewhere in this Plan. All vaccine research and development are included under Goal 1 as the approach to achieving these objectives and the key stakeholders are not different for the United States and the rest of the world. By contrast, issues related to vaccine safety, communications, and program implementation are included under the Global Immunization goal as well as under other goals of the Plan. Whereas many of the objectives in these areas are similar for the U.S. and abroad, the strategies differ as internationally, U.S. stakeholders focus on partnerships and providing assistance rather than on direct implementation as described elsewhere in the Plan” (HHS, 2008:56). 19 Strategy 1.2.2: Conduct and support expanded vaccine research to meet medical and public health needs of specific populations including neonates, infants, the elderly, pregnant women, and immunocompromised individuals; Strategy 1.4.7: Establish and strengthen partnerships to address urgent needs in vaccine research and development; and Strategy 1.4.8: Establish alternative development and manufacturing approaches to support licensure for those vaccines that have a limited market.
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