1

Introduction: New Vaccines and SMART Vaccines

Decision making is not always easy, especially under complex circumstances. Deciding which vaccines—or which of any sort of health care products or services—that one should invest in requires a complex assessment of alternatives. And the planning process, which can consume massive amounts of resources, generally must contend with a variety of uncertainties and sometimes also biases and bits of “conventional wisdom” that may actually be incorrect.

New vaccine development is a demanding process. It is long and often arduous, and few appreciate the amount of work and resources that go toward producing and delivering what may seem to many like a trivial matter—say, half a milliliter of fluid contained in a vaccine vial or ampoule. The process typically consumes hundreds of millions of dollars, and its success relies on the co-evolution of scientific understanding, regulatory environment and requirements, production technologies, public health needs, human resource management, and often an understanding of the culture of the intended recipients of vaccination (Rappuoli et al., 2011).

The process for developing new vaccines has changed significantly over the last three decades (see Figure 1-1). In the 1980s the major obstacles for new vaccines were on the discovery side, while development was relatively easy, and the licensing process required only several hundreds of subjects evaluated in clinical trials (Rappuoli and Alderem, 2011).

During the 1990s many new promising technologies, including recombinant DNA, conjugation, and genomics, emerged and aided vaccine discovery (Bagnoli et al., 2011). However, during the same period the timelines and budgets required for the development of vaccines soared



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 13
1 Introduction: New Vaccines and SMART Vaccines Decision making is not always easy, especially under complex circum- stances. Deciding which vaccines—or which of any sort of health care products or services—that one should invest in requires a complex assess- ment of alternatives. And the planning process, which can consume mas- sive amounts of resources, generally must contend with a variety of uncer- tainties and sometimes also biases and bits of “conventional wisdom” that may actually be incorrect. New vaccine development is a demanding process. It is long and often arduous, and few appreciate the amount of work and resources that go toward producing and delivering what may seem to many like a trivial matter—say, half a milliliter of fluid contained in a vaccine vial or ampoule. The process typically consumes hundreds of millions of dollars, and its suc- cess relies on the co-evolution of scientific understanding, regulatory envi- ronment and requirements, production technologies, public health needs, human resource management, and often an understanding of the culture of the intended recipients of vaccination (Rappuoli et al., 2011). The process for developing new vaccines has changed significantly over the last three decades (see Figure 1-1). In the 1980s the major obstacles for new vaccines were on the discovery side, while development was rela- tively easy, and the licensing process required only several hundreds of sub- jects evaluated in clinical trials (Rappuoli and Alderem, 2011). During the 1990s many new promising technologies, including recombinant DNA, conjugation, and genomics, emerged and aided vac- cine discovery (Bagnoli et al., 2011). However, during the same period the timelines and budgets required for the development of vaccines soared 13

OCR for page 13
14 RANKING VACCINES: A Prioritization Software Tool 1980 2010 Time (years) FIGURE 1-1 Change in the time and resources required for vaccine discovery and development from 1980 to 2010. In the 1980s vaccine discovery required a long time, while development periods were relatively short. More recently, the time involved in new vaccine discovery has shortened dramati- cally due to the availability of various new technologies. However, in the meantime the regulatory requirements have lengthened the development timelines substantially. This results in longer times for vaccine licensure and significant increases in development costs. SOURCE: Adapted from Rappuoli and Alderem, 2011. (Milstien and Candries, 2002). The burgeoning research and development budgets coupled with increasing regulatory complexity and the increased time required for the development of a new vaccine made the decision pro- cess very challenging and necessitated the use of sophisticated models to predict the returns on the investment. Moreover, while high-income countries face greatly increased lengths of time and various financial and scientific challenges when devel- oping new vaccines, as illustrated in Figure 1-1, developing vaccines for use only in low-income countries is perhaps even more challenging, as there are fewer mechanisms in place to develop those vaccines (Batson, 2005; Rappuoli and Alderem, 2011). It may take a number of additional years after a vaccine is commercially available in high-income countries to introduce the same vaccine in low-income countries. And even if a vaccine is avail- able in high-income countries, it may be the case that models are unable to justify the investment required for the development of the same vaccine in low-income countries, where they may not be a profitable market; this is a particular challenge with innovative vaccines. An example is a conju- gate vaccine against meningococcus A that was developed specifically for

OCR for page 13
Introduction: New Vaccines and SMART Vaccines 15 a low-income region of sub-Saharan Africa. The development effort was made possible only through the work of a vaccine manufacturer from a low- income country with the support of the Bill & Melinda Gates Foundation— even though these meningococcal conjugates were already developed and licensed in high-income countries (Bishai et al., 2011). This inequity between high- and low-income countries needs to be captured within decision-support tools in order to emphasize economic and health returns. Another example that illustrates the need for decision-support tools concerns the introduction of improved vaccines. Older vaccines continue to be used because the business models are not able to justify the invest- ment necessary to improve those products. An example is the pertussis vac- cine. Because of reactions associated with the older whole-cell pertussis vaccines developed and licensed in the late 1940s, new vaccine develop- ment became a high priority for research funding agencies, regulatory bod- ies, and industry in the 1980s. New, more highly purified acellular vaccines were developed and licensed in the mid-1990s and were shown to have an excellent safety profile. After that success, interest in the science of pertus- sis decreased, and little effort was made to improve the vaccine further. The situation has recently changed with the finding that the immunity created by the acellular vaccines appears to be not as long-lasting as the immunity from the whole cell vaccine. Now, with the shortcomings of the pertussis vaccines apparent, funding agencies are being asked to support research in the biology of pertussis, and regulatory agencies are being requested to find innovative ways to license new pertussis vaccines in the absence of efficacy trials. However, private industry has little incentive to invest in this work because a company cannot justify investing in a new full-fledged develop- ment program without proof of concept, a clear regulatory strategy, a price point advantage or an authoritative use recommendation that will generate a return on its investment. Yet another example illustrating the need for a comprehensive pri- oritization model concerns discounting, which typically puts vaccination at a disadvantage to therapeutic interventions in a company’s financial cal- culations. In most calculations the benefit of an intervention is captured in full for the first year and then discounted in following years. This is not an issue for a therapeutic intervention, where the cost occurs very close to the benefit. However, it is an issue for vaccines because the benefits occur many years after vaccination. Therefore, applying similar discounting methods to both vaccines and therapeutics—which is typical—can have a strong influ- ence on the outcome of models that are based solely on cost-effectiveness and thus can profoundly affect the resulting decisions (Bloom et al., 2005). Finally, there are some features that are unique to vaccination and

OCR for page 13
16 RANKING VACCINES: A Prioritization Software Tool that make impact assessment even more complicated. One of these is the concept of herd immunity, which refers to the fact that vaccines protect not only the vaccinated subjects but also unvaccinated people by reduc- ing the circulation of a pathogen (Drummond et al., 2007). This benefit is realized several years after implementation of the primary intervention and is often not included in most cost-effectiveness models. Furthermore, if herd immunity is included in the model, it is discounted, thus reducing the calculated true value of the intervention. Yet herd immunity can have major benefits. An extreme example is the eradication of the pathogen that causes a disease. For example, smallpox has been eradicated, and polio is on the verge of eradication (Brilliant and Foege, 2013; Tomori, 2011). Thus, it is important that the impact of herd immunity be adequately captured in decision models. Today, decision-support frameworks provide guidance in planning and prioritizing many of the above-mentioned scenarios. However, those involved in such assessments plan and prioritize development and imple- mentation processes in their own ways, which are sometimes proprietary. Decision making related to the development and implementation of vaccines is complex and involves many stakeholders, including vaccine manufactur- ers, public and private funding agencies, nongovernmental organizations, regulators, and purchasers. Each of these partners needs tools or mecha- nisms to compare the relative benefits of different vaccines in their port- folio, of new vaccines that may become available, and of vaccines weighed against other interventions. Decision making involves understanding the existing and emerging landscape of vaccine development, the real benefits that vaccination brings to society, and the limitations of the decision models available today. Sound decision making sometimes also involves persuading others; for example, a minister of health may need to convince the minister of finance about the value of a given vaccine (or a vaccination program) and why it should be prioritized versus other interventions. Decision makers in different areas look at different factors in making their decisions. Industrial executives, for instance, may need to first evalu- ate the technical feasibility and the projected efficacy of a new vaccine and then decide whether the investment in a particular vaccine provides better return to the investors than an investment in other options, such as thera- peutic drugs, where profit margins are usually higher. Funders of vaccine research, development, and implementation prioritize different vaccines in different countries for different reasons. A tool that facilitates an assess- ment of the decision-making process of all the diverse, independent, and sometimes conflicting stakeholders would greatly improve the quality of the discussions and decisions related to individual and public health pri-

OCR for page 13
Introduction: New Vaccines and SMART Vaccines 17 orities. This is reinforced by the fact that all stakeholders operate under conditions of limited resources and must choose among alternatives. The need for a better and more comprehensive tool that can support different entities is also underscored by the abundance of varying perspec- tives within the vaccine enterprise. The stakeholders involved in vaccine development range from government entities to public and private funding organizations, vaccine manufacturers, and vaccine program implementa- tion leaders. It was in order to accommodate the many different scenarios and even more viewpoints that the Institute of Medicine (IOM) Committee on Identifying and Prioritizing New Vaccines for Development designed SMART Vaccines. This software has been developed, keeping various stakeholders in mind, to provide a more consistent method for informing decisions and to offer an analytical base for reaching individual or collec- tive decisions. Study Context and Scope A critical development in the realm of vaccine policy was the release of the 2010 National Vaccine Plan by the U.S. Department of Health and Human Services’ National Vaccine Program Office (NVPO) (HHS, 2010). The plan’s various goals and priorities make it compellingly clear that all strata of the vaccine enterprise must work toward the development of safe, effective vaccines that are important to global public health. The first goal of the plan is to “develop new and improved vaccines,” with one of the correspond- ing implementation priorities relating to the development of a catalogue of vaccine targets that are domestically and globally important (highlighted as bold text in Box 1-1). In order to achieve the first goal of the National Vaccine Plan 2010, the NVPO requested that the IOM conduct a study to create a framework for prioritizing vaccines. This work has been carried out in two phases, whose places in the overall plan are shown in Figure 1-2, which outlines the tasks required to reach the ultimate vision of creating a catalogue of prior- ity vaccines for both domestic and international importance. The Phase I committee developed a multi-attribute utility framework and a blueprint for software named the Strategic Multi-Attribute Ranking Tool for Vac- cines—or SMART Vaccines Beta. The Phase II committee continued the Phase I committee’s work by refining the model underpinning SMART Vaccines Beta. (See Box S-1 for the Statement of Task.) The current enhanced version of the software, SMART Vaccines 1.0, is a product of continuous stakeholder feedback coupled with the committee’s deliberations and has been made available for public use.

OCR for page 13
18 RANKING VACCINES: A Prioritization Software Tool BOX 1-1 The 2010 National Vaccine Plan U.S. Department of Health and Human Services Goals 1. Develop new and improved vaccines. 2. Enhance the vaccine safety system. 3. Support communications to enhance informed vaccine decision making. 4. Ensure a stable supply of, access to, and better use of recom- mended vaccines in the United States. Priorities A. Develop a catalogue of priority vaccine targets of domestic and global health importance. B. Strengthen the science base for the development and licensure of new vaccines. C. Enhance timely detection and verification of vaccine safety sig- nals and develop a vaccine safety scientific agenda. D. Increase awareness of vaccines, vaccine-preventable diseases, and the benefits/risks of immunization among the public, provid- ers, and other stakeholders. E. Use evidence-based science to enhance vaccine-preventable disease surveillance, measurement of vaccine coverage, and measurement of vaccine effectiveness. F. Eliminate financial barriers for providers and consumers to facili- tate access to routinely recommended vaccines. G. Create an adequate and stable supply of routinely recommended vaccines and vaccines for public health preparedness. H. Increase and improve the use of interoperable health information technology and electronic health records. I. Improve global surveillance for vaccine-preventable diseases and strengthen global health information systems to monitor vaccine coverage, effectiveness, and safety. J. Support global introduction and availability of new and under- utilized vaccines to prevent diseases of public health importance.

OCR for page 13
Introduction: New Vaccines and SMART Vaccines 19 Step 1 Step 2 Step 3 Phase I Phase III Create and Validate Execute and the Model Populate the Catalogue of Priority SMART Vaccines Beta Model Vaccine Candidates Phase II of Domestic and Data Architecture Global Importance Enhance the and Software Model Usability Studies SMART Vaccines 1.0 FIGURE 1-2 Steps needed to achieve the first goal of the National Vaccine Plan, according to the National Vac- cine Program Office of the Department of Health and Human Services. Phase I in Step 1 resulted Figure 1-2.eps in the Institute of Medicine’s Ranking Vaccines: A Prioritization Framework as well as the blueprint of the software SMART Vaccines Beta (IOM, 2012). Phase II in Step 1 (highlighted in yellow) relates to this report, Ranking Vaccines: A Prioritization Software Tool, and SMART Vaccines 1.0. Step 2 (Phase III) involves the data architecture and software usability studies, with Step 3 efforts ulti- mately resulting in a catalogue of domestically and globally significant vaccine candidates. The committee has also expanded the datasets available for use with the software and evaluated three additional vaccine candidates for the United States and South Africa. The combined group of vaccine candidates con- sists of vaccines for influenza, tuberculosis, group B streptococcus, human papillomavirus, pneumococcal infection, and rotavirus. Study Process and Feedback from Stakeholders In the summer of 2012, immediately after the release of the Phase I report Ranking Vaccines: A Prioritization Framework (IOM, 2012), an 18-member committee was formed that contained some members who had served on the Phase I committee plus some new members. (Appendix F contains the biographical information of the members.) To accomplish its task, the com- mittee held three committee meetings as well as several ad hoc subgroup committee meetings held via teleconference. The committee worked with eight consultants, one of whom assisted with modeling and programming, while the others helped to evaluate an early prototype version of SMART Vaccines 1.0. As with any software application, the development of SMART Vac- cines followed an iterative process. The committee went through mul- tiple versions of the software, each of which took into account feedback and suggested refinements from stakeholders. To gather feedback on the

OCR for page 13
20 RANKING VACCINES: A Prioritization Software Tool BOX 1-2 Framing Questions for Stakeholders’ Feedback Usefulness: Do you think SMART Vaccines could be useful to you as you make decisions regarding new vaccine development and pri- oritization? Please elaborate on how you might use it and for what purposes. How does this approach complement and/or differ from your current decision-making approach? Usability: Does SMART Vaccines cover the most relevant issues related to vaccine development and prioritization? Is the current software version user-friendly? Please comment on the ease of under­ tanding how to use it and the demands on the user.  s Data Library: How should the committee address the intensive needs for data inputs into the model? How should the user groups think about data requirements and resources for data collection and standardization? Application Development: In what ways can SMART Vaccines be enhanced? Outreach: What advice can you give regarding how best to engage  various user groups and decision makers to use—and ­ urther f develop—SMART Vaccines? model, software, and data, the committee organized and conducted several feedback-gathering sessions with interested stakeholders and the public. As part of the efforts to gather public feedback, the committee mem- bers used a variety of formats for demonstrating the concept and utility of SMART Vaccines. Webinars, teleconferences, plenary talks, group dis- cussions, and presentations were offered for a variety of audiences that included representatives from federal advisory groups, professional soci- eties, policy groups, international governmental agencies, private industry, and philanthropic and trade organizations. The committee also organized an international stakeholder workshop to obtain additional feedback for

OCR for page 13
Introduction: New Vaccines and SMART Vaccines 21 use in improving the functionality of SMART Vaccines. (See Appendix E for a listing of speakers.) The questions posed to the speakers fell into five main categories: usefulness, preliminary usability, data needs, application development, and possibilities for outreach (described in Box 1-2). In the course of numerous public presentations about SMART Vaccines (based on the Phase I report), the committee members received many comments and questions. Table 1-1 contains a listing of the most common questions and comments from stake- holders, along with the committee’s response and commentary. The committee took the gathered feedback into account in its delib- erations on refining the model, on informing the data collection for addi- tional vaccine candidates, and on redesigning the software interface. Those efforts are detailed in Chapter 2.

OCR for page 13
22 RANKING VACCINES: A Prioritization Software Tool TABLE 1-1 Frequently Asked Questions and the Committee’s Responses Stakeholder Question Committee’s Response Is there not a risk that Technically yes, but SMART Vaccines makes the multi-attribute explicit what has previously remained hidden utility model underlying from view. The committee anticipates and SMART Vaccines can be hopes that when various users begin to “gamed” so that users discuss the rankings they have produced using get the rankings they SMART Vaccines, others will insist that each wanted in the first place? user make clear the levels of attributes they have assigned to various vaccine candidates (including cost, efficacy, coverage, side effects) and the multi-attribute utility value weights. With these data available for open discussion, various parties can compare their inputs and results and reach an understanding on what drives each user’s results. Should the most Previous ranked lists, including the 1985–1986 important variable in and 2000 reports from the Institute of the system be life-years Medicine, used a single attribute for vaccine saved? Why bother prioritization: The 1985–1986 reports used with anything else? a metric similar to life-years saved, and the 2000 report used an efficiency measure of cost-effectiveness measured as cost per quality-adjusted life year (IOM, 1985, 1986, 2000). But both studies stated clearly in their reports that many other issues would guide final decision making on vaccine priorities. SMART Vaccines seeks to make explicit exactly how these “other issues” affect the decisions. There will still remain issues and attributes not taken into account by SMART Vaccines, but the committee believes that making these considerations explicit will improve decision making and communication among affected and interested parties. SMART Vaccines is of Yes. The committee not only agrees with limited use without much this, but hopes that the creation of SMART better data, is it not? Vaccines will accelerate the production of necessary data. In the absence of such data, decisions continue to be made, and the committee believes that decision making about vaccine priority ranking will improve with the production of better data and the use of a carefully structured model such as SMART Vaccines. This report concludes with some strategic steps that the committee believes will greatly enhance the production of high- quality datasets for use in SMART Vaccines.

OCR for page 13
Introduction: New Vaccines and SMART Vaccines 23 TABLE 1-1 Continued Stakeholder Question Committee’s Response It is unusual to place SMART Vaccines does not create a classic “corporate profits” into social welfare function. Users can do such a social welfare function by choosing attributes in the multi-attribute such as created by utility model and weights attached to SMART Vaccines, is it not? those attributes that are consistent with traditional economic models of social welfare maximization. But it is not limited to that use. For example, vaccine manufacturers can also use SMART Vaccines to measure value from their own viewpoint (including, presumably, corporate profitability) and also to help them understand the values and resultant rankings of their potential customers. SMART Vaccines creates To some extent, yes, but if one carefully a large data burden on assesses the data needed to analyze the users, does it not? related issues intelligently, it becomes apparent that the data needs are driven by the intrinsic issue at hand, not the software. The committee has sought to make the best possible use of extant databases that will help SMART Vaccine users simplify the data burden, including, for example, population data (from the World Health Organization) and other data on burden of disease and related issues. Would not the rankings Yes, but that remains true whether people from SMART Vaccines have used SMART Vaccines or not. It become useless if, for cannot predict the emergence of disruptive example, some new technologies. It can readily re-estimate treatment emerges for the priority scores in the presence of new a disease for which a information, and all rankings should be re- new vaccine is under calculated when conditions surrounding development? any vaccine’s potential use change. How can you expect In general, the committee believes that high- decision makers to deal level decision makers will not in fact have with the complexity of to deal with many facets of the software’s this software program? complexity. More likely, specialized assistants to decision makers will create or import relevant data and possibly even carry out preliminary analyses using weights specified by the decision maker. The current version of SMART Vaccines provides entry points into the software at appropriate points for each possible type of user, ranging from technical data specialists to final decision makers. continued

OCR for page 13
24 RANKING VACCINES: A Prioritization Software Tool TABLE 1-1 Continued Stakeholder Question Committee’s Response How can I interpret Each user’s particular set of values and what the scores from weights helps define the scale for the SMART Vaccines mean? final priority score, so users cannot compare scores from one user to another unless they use the same attributes and endpoints. This is a standard feature of multi-attribute utility models.  Some users have found it useful to think about the priority scores in the same way that we think about reports of temperature. In a Fahrenheit scale the difference between 50°F and 70°F (20 degrees) has the same meaning as the difference between 20°F and 40°F. However, in the Fahrenheit scale 40°F is not twice as hot as 20°F. Similarly, on a Celsius scale the difference between 20°C and 30°C (10 degrees) has the same meaning as the difference between 10°C and 20°C, but 20°C is not twice as hot as 10°C. Furthermore, 20°C and 20°F do not have the same meaning. These differences do not make thermometers useless, but they do require an “anchor” to interpret them. With thermometers, we can use standard reference points to help understand what 20°F and 20°C mean. We know that water freezes at 0°C and boils at 100°C, and similarly that water freezes at 32°F and boils at 212°F. Knowing these two pairs of values allows us to make direct comparisons between Fahrenheit and Celsius values, and we can calculate that they have the same meaning at only one temperature—that is, minus 40°C has the same value as minus 40°F. Who is expected Potential users of SMART Vaccines to use SMART (individually or collaboratively) include Vaccines and why? decision makers in a wide range of constituencies: federal and private research groups, funders, vaccine manufacturers, purchasers of vaccines, regulators, and nongovernmental groups. SMART Vaccines offers a new framework that could help provide a new standard for decision making among various stakeholders in many circumstances such as decision making under opacity; prioritizing under constrained resources, complexities associated with globalization, economies, and health. Furthermore, changing realities need decision models to be refreshed, which is what this tool offers—a dynamic, living decision-support framework that can be updated as new data, diseases and potential vaccine candidates emerge.