Vaccine 32 (2014) 1029–1030
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Letter to the Editor Vaccines at what price? Vaccines have long been recognized as one of the interventions with the best economic value for reducing human disease burden. However, cost effectiveness “standards” as the overriding criterion for determining whether to recommend vaccines for widespread use are now creating a serious dilemma for the development of new vaccines. Serogroup B meningococcal disease is the most common cause of serious meningococcal disease in infants in industrialized countries, is associated with high mortality rates (5–10%) despite treatment and many of the survivors (10–20%) are left with permanent sequelae [1]. Recently, a safe vaccine that could prevent such a health burden was not recommended (at least for now) for incorporation into a national immunization program because it did not meet criteria considered “cost-effective” [2,3]. This decision has implications well beyond the prevention of meningococcal B disease. Cost-effectiveness is certainly an important factor to consider in making immunization policy. Manufacturers should be incentivized to provide vaccines at as low a price as feasible to increase the cost-effectiveness of their products. However, national decisions to incorporate a vaccine into a national immunization program based solely on estimates of “cost-effectiveness” are unwise and can derail development of other critically important future vaccines. Indeed, the US Institute of Medicine (IOM), in its recent report, “Ranking Vaccines”, allows users of the tool for prioritizing vaccine development to include both quantitative and qualitative values [4]. For example, the IOM model allows values of public concerns (e.g., disease raises fear and stigma in the public, emerging or biological threat agents) as potential determinants in deciding which vaccines should receive the highest priorities for development. Making “cost-effectiveness” the deciding bar for public health recommendations and vaccine policy is a slippery slope potentially stifling future vaccine development and leading to a continuation or reemergence of disease burdens despite knowledge and the product development paths that could be used to create effective and safe vaccines. One of the most commonly used economic analyses is costutility analysis in which cost per Disability Adjusted Life Year (DALY) averted or cost per Quality Adjusted Life Year (QALY) gained for given interventions are compared between various interventions. As noted by Miller et al. for vaccines [5] and in a broader context by Hirth et al. [6], many subjective and ethical assumptions underlie the DALY and QALY constructs and their economic value that can complicate interpretation and what the comparisons really mean. Cost-effectiveness analyses should not be viewed as fixed; the model variables may change over time (e.g., changing disease incidence), key variables for which precise data are not available must be estimated based on expert opinion or other methods (not an infrequent occurrence and thus can be incorrect), and unknowns that dramatically alter such analyses (e.g., population impact of vaccine effectiveness, 0264-410X/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.12.066
duration of vaccine-induced immunity) are always lurking. For example, predictions about the “cost-effectiveness” of the pneumococcal conjugate PCV7 prior to introduction were wrong (and could have led to a vote of rejection of the vaccine) because the significant impact of herd protection on the unvaccinated population was not recognized until after vaccine introduction [7]. Thus, the use of pneumococcal conjugate vaccines, now critical to the worldwide control of pneumococcal disease, may have been delayed or stalled if the decision had been made solely on original projections of “cost-effectiveness.” In the US, the vaccine was recommended for universal use in children in 2000 taking into account many factors including but not limited to whether the vaccine would be cost-saving. For serogroup B meningococcal disease, two cost effectiveness analyses contained in the Joint Committee on Vaccines and Immunisation (JCVI) in the United Kingdom report [2] reached very different conclusions. Uncertainties in estimating the underappreciated long term sequelae of meningococcal disease; the significant family, community and societal impact; litigation costs and inclusion or not of other variables were critical to the different conclusions in two different cost-effectiveness analyses [2]. While models and assumptions that provide data for cost-effectiveness analyses may lead to different results, it is critical that advisory committees considering such data have standards that must be met for an analysis to be presented to them. The US Advisory Committee on Immunization Practices (ACIP) has developed such guidance (http://www.cdc.gov/vaccines/acip/committee/guidance/ economic-studies.html). Further, an important concept in public health decision making regarding vaccines is the “moral imperative or willingness to pay” [5,6]. This concept may trump or carry greater weight in decisionmaking, even when cost-effectiveness is considered unfavorable. The IPV versus OPV polio vaccine decision in the US is an example of this kind of decision making. The ACIP decided to recommend incorporation of IPV into the childhood immunization schedule replacing OPV, despite the fact that the estimates that the cost per case of vaccine-associated paralytic polio (VAPP) prevented were on the order of $3 million [8]. The importance of values beyond cost-effectiveness was recognized by the US Congress in enacting legislation to establish the Vaccines for Children (VFC) Program [9]. The statement of managers, which explains the legislative intent, empowers the ACIP to incorporate vaccines into the program, bypassing traditional budgetary processes and uses. As an example, a safer but potentially more expensive vaccine, one that would be best for public health, may require an increase in the federal budget. The devastation meningococcal disease can have on children, families and societies goes well beyond “cost effectiveness” and is a strong case for the prevention of this disease if effective and safe vaccines are available. For example, meningococcal vaccine was recommended by the ACIP for college freshman living in dormitories despite the fact that the costs to prevent a case, a death, or per Life Year Saved (LYS) were $617,000–$1.85
1030
Letter to the Editor / Vaccine 32 (2014) 1029–1030
million, $6.8–$20.4 million, and $62,042–$489,185, respectively (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm# tab6). Disease eradication is another place where economic analysis alone could prevent achieving the goal. While the overall program is cost-effective, the last chains of transmission are usually the most difficult to terminate and the cost per case prevented at the end is likely to be far more expensive than early chains. Termination of the program prematurely because of the high cost of the final stages of eradication could cause failure of the whole program with resurgence of disease. A second dose of measles, mumps, rubella (MMR) vaccine was recommended to help achieve measles elimination despite the fact that a first dose provided about 95% or greater protection, so maximal impact of the second dose for the individual would be enhancing their protection rate by 5% (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm# tab6). A system for public prioritization of new vaccines is needed with defined models to incentivize manufacturers even if the need as reflected in the epidemiology of a disease radically changes. Project Bioshield in the US is one example. The combination of the serogroup B vaccine components with an A, C, Y, W conjugate as a single vaccine to prevent meningococcal disease could also be a major way to counter the current meningococcal debate. Also, more creative strategies are needed that lead to lower costs of vaccines. The development of the successful MenAfrivac serogroup A meningococcal conjugate for Africa is a very important example [10]. The IOM Smart Vaccines tool appears promising in giving vaccine developers and public health decision-makers guidance on which vaccines should be prioritized. The IOM tool helps evaluate and weigh the multiple factors which should be considered in prioritizing which vaccines should be developed [4]. Inputs into key variables in Smart Vaccines can be gained through surveys, focus groups and other means. Groups that should be involved include experts in the disease and vaccine at issue, vaccinology scientists, public and private health officials and practitioners, and the general public. These considerations should be incorporated into decisions to recommend the use of such vaccines once developed. Regardless, the epidemiology and burden of a disease may change during the decades it usually takes to develop a new vaccine. Hence, there may be substantial investments in developing a vaccine that by the time of availability, the vaccine is no longer considered a priority for use. Thus, mechanisms to compensate for these major investments are needed or we risk dis-incentivizing development of all vaccines. Given the history of success of effective and safe vaccines, the continuing significant worldwide burden of infectious diseases and the use of vaccines for cancer and other diseases, we need to
not impede future vaccine development and introduction. A system that prioritizes vaccine development and use, taking into account considerations including but not limited to cost-effectiveness is critical to obtaining optimal, publically supported, disease prevention through vaccines. This provides assurance that the vaccines needed are developed and available for use. The current emergency use of a new serogroup B vaccine to address an outbreak at Princeton University is one example [11]. References [1] Cohn AC, Messonnier NE. Inching toward a serogroup B meningococcal vaccine for infants. JAMA 2012;307(6):614–5. [2] Joint Committee on Vaccination and Immunisation (JCVI) interim position statement on the use of Bexsero meningococcal B vaccine in the UK. Gov.UK. Department of Health, 24 July 2013. [3] Moxon R, Snape MD. The price of prevention: what now for immunisation against meningococcus B. Lancet 2013;382(9890):369–70. [4] Madhavan G, Sangha K, Phelps C, et al, Committee on Identifying and Prioritizing New Preventive Vaccines for Development, editors. Ranking vaccines: a prioritization software tool: phase II: prototype of a decision support system. Institute of Medicine, National Academies Press; 2013. p. 1–160. [5] Miller MA, Hinman AR. Economic analyses of vaccine policies. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 6th ed. Elsevier; 2013. p. 1413–26. [6] Hirth RA, Chernew ME, Miller E, Fendrick AM, Weissert WG. Willingness to pay for a quality-adjusted life year: in search of a standard. Med Decis Making 2000;20:332. [7] Ray GT, Whitney CG, Fireman BH, Ciuryla V, Black SB. Cost-effectiveness of pneumococcal conjugate vaccine evidence from the first 5 years of use in the United States incorporating herd effects. Pediatr Infect Dis 2006;25:494–501. [8] Miller MA, Sutter RW, Strebel PM, Hadler SC. Cost-effectiveness of incorporating inactivated poliovirus vaccine into the routine childhood immunization schedule. JAMA 1996;276(12):967–71. [9] Centers for Disease Control and Prevention: Vaccines for Children Program. VFC program distribution of pediatric vaccines. http://www.cdc.gov/ vaccines/programs/vfc/about/distribution.html [accessed 29.11.2013]. [10] Centers for Disease Control and Prevention (CDC). Serogroup A meningococcal conjugate vaccine coverage after the first national mass immunization campaign-Burkina Faso, 2011. MMWR Morb Mortal Wkly Rep 2012;61(50):1022–4. [11] Schwartz JL. Outbreaks, ethics and economics. Chronicle of Higher Education 2013, December 9.
D.S. Stephens ∗ R. Ahmed W.A. Orenstein Emory Vaccine Center, Emory University School of Medicine, United States ∗ Corresponding
author. Tel.: +1 404 727 8357; fax: +1 404 778 5434. E-mail address: [email protected] (D.S. Stephens) 30 September 2013 Available online 9 January 2014
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Letter to the Editor Vaccines at what price? Vaccines have long been recognized as one of the interventions with the best economic value for reducing human disease burden. However, cost effectiveness “standards” as the overriding criterion for determining whether to recommend vaccines for widespread use are now creating a serious dilemma for the development of new vaccines. Serogroup B meningococcal disease is the most common cause of serious meningococcal disease in infants in industrialized countries, is associated with high mortality rates (5–10%) despite treatment and many of the survivors (10–20%) are left with permanent sequelae [1]. Recently, a safe vaccine that could prevent such a health burden was not recommended (at least for now) for incorporation into a national immunization program because it did not meet criteria considered “cost-effective” [2,3]. This decision has implications well beyond the prevention of meningococcal B disease. Cost-effectiveness is certainly an important factor to consider in making immunization policy. Manufacturers should be incentivized to provide vaccines at as low a price as feasible to increase the cost-effectiveness of their products. However, national decisions to incorporate a vaccine into a national immunization program based solely on estimates of “cost-effectiveness” are unwise and can derail development of other critically important future vaccines. Indeed, the US Institute of Medicine (IOM), in its recent report, “Ranking Vaccines”, allows users of the tool for prioritizing vaccine development to include both quantitative and qualitative values [4]. For example, the IOM model allows values of public concerns (e.g., disease raises fear and stigma in the public, emerging or biological threat agents) as potential determinants in deciding which vaccines should receive the highest priorities for development. Making “cost-effectiveness” the deciding bar for public health recommendations and vaccine policy is a slippery slope potentially stifling future vaccine development and leading to a continuation or reemergence of disease burdens despite knowledge and the product development paths that could be used to create effective and safe vaccines. One of the most commonly used economic analyses is costutility analysis in which cost per Disability Adjusted Life Year (DALY) averted or cost per Quality Adjusted Life Year (QALY) gained for given interventions are compared between various interventions. As noted by Miller et al. for vaccines [5] and in a broader context by Hirth et al. [6], many subjective and ethical assumptions underlie the DALY and QALY constructs and their economic value that can complicate interpretation and what the comparisons really mean. Cost-effectiveness analyses should not be viewed as fixed; the model variables may change over time (e.g., changing disease incidence), key variables for which precise data are not available must be estimated based on expert opinion or other methods (not an infrequent occurrence and thus can be incorrect), and unknowns that dramatically alter such analyses (e.g., population impact of vaccine effectiveness, 0264-410X/$ – see front matter © 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.12.066
duration of vaccine-induced immunity) are always lurking. For example, predictions about the “cost-effectiveness” of the pneumococcal conjugate PCV7 prior to introduction were wrong (and could have led to a vote of rejection of the vaccine) because the significant impact of herd protection on the unvaccinated population was not recognized until after vaccine introduction [7]. Thus, the use of pneumococcal conjugate vaccines, now critical to the worldwide control of pneumococcal disease, may have been delayed or stalled if the decision had been made solely on original projections of “cost-effectiveness.” In the US, the vaccine was recommended for universal use in children in 2000 taking into account many factors including but not limited to whether the vaccine would be cost-saving. For serogroup B meningococcal disease, two cost effectiveness analyses contained in the Joint Committee on Vaccines and Immunisation (JCVI) in the United Kingdom report [2] reached very different conclusions. Uncertainties in estimating the underappreciated long term sequelae of meningococcal disease; the significant family, community and societal impact; litigation costs and inclusion or not of other variables were critical to the different conclusions in two different cost-effectiveness analyses [2]. While models and assumptions that provide data for cost-effectiveness analyses may lead to different results, it is critical that advisory committees considering such data have standards that must be met for an analysis to be presented to them. The US Advisory Committee on Immunization Practices (ACIP) has developed such guidance (http://www.cdc.gov/vaccines/acip/committee/guidance/ economic-studies.html). Further, an important concept in public health decision making regarding vaccines is the “moral imperative or willingness to pay” [5,6]. This concept may trump or carry greater weight in decisionmaking, even when cost-effectiveness is considered unfavorable. The IPV versus OPV polio vaccine decision in the US is an example of this kind of decision making. The ACIP decided to recommend incorporation of IPV into the childhood immunization schedule replacing OPV, despite the fact that the estimates that the cost per case of vaccine-associated paralytic polio (VAPP) prevented were on the order of $3 million [8]. The importance of values beyond cost-effectiveness was recognized by the US Congress in enacting legislation to establish the Vaccines for Children (VFC) Program [9]. The statement of managers, which explains the legislative intent, empowers the ACIP to incorporate vaccines into the program, bypassing traditional budgetary processes and uses. As an example, a safer but potentially more expensive vaccine, one that would be best for public health, may require an increase in the federal budget. The devastation meningococcal disease can have on children, families and societies goes well beyond “cost effectiveness” and is a strong case for the prevention of this disease if effective and safe vaccines are available. For example, meningococcal vaccine was recommended by the ACIP for college freshman living in dormitories despite the fact that the costs to prevent a case, a death, or per Life Year Saved (LYS) were $617,000–$1.85
1030
Letter to the Editor / Vaccine 32 (2014) 1029–1030
million, $6.8–$20.4 million, and $62,042–$489,185, respectively (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm# tab6). Disease eradication is another place where economic analysis alone could prevent achieving the goal. While the overall program is cost-effective, the last chains of transmission are usually the most difficult to terminate and the cost per case prevented at the end is likely to be far more expensive than early chains. Termination of the program prematurely because of the high cost of the final stages of eradication could cause failure of the whole program with resurgence of disease. A second dose of measles, mumps, rubella (MMR) vaccine was recommended to help achieve measles elimination despite the fact that a first dose provided about 95% or greater protection, so maximal impact of the second dose for the individual would be enhancing their protection rate by 5% (http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5407a1.htm# tab6). A system for public prioritization of new vaccines is needed with defined models to incentivize manufacturers even if the need as reflected in the epidemiology of a disease radically changes. Project Bioshield in the US is one example. The combination of the serogroup B vaccine components with an A, C, Y, W conjugate as a single vaccine to prevent meningococcal disease could also be a major way to counter the current meningococcal debate. Also, more creative strategies are needed that lead to lower costs of vaccines. The development of the successful MenAfrivac serogroup A meningococcal conjugate for Africa is a very important example [10]. The IOM Smart Vaccines tool appears promising in giving vaccine developers and public health decision-makers guidance on which vaccines should be prioritized. The IOM tool helps evaluate and weigh the multiple factors which should be considered in prioritizing which vaccines should be developed [4]. Inputs into key variables in Smart Vaccines can be gained through surveys, focus groups and other means. Groups that should be involved include experts in the disease and vaccine at issue, vaccinology scientists, public and private health officials and practitioners, and the general public. These considerations should be incorporated into decisions to recommend the use of such vaccines once developed. Regardless, the epidemiology and burden of a disease may change during the decades it usually takes to develop a new vaccine. Hence, there may be substantial investments in developing a vaccine that by the time of availability, the vaccine is no longer considered a priority for use. Thus, mechanisms to compensate for these major investments are needed or we risk dis-incentivizing development of all vaccines. Given the history of success of effective and safe vaccines, the continuing significant worldwide burden of infectious diseases and the use of vaccines for cancer and other diseases, we need to
not impede future vaccine development and introduction. A system that prioritizes vaccine development and use, taking into account considerations including but not limited to cost-effectiveness is critical to obtaining optimal, publically supported, disease prevention through vaccines. This provides assurance that the vaccines needed are developed and available for use. The current emergency use of a new serogroup B vaccine to address an outbreak at Princeton University is one example [11]. References [1] Cohn AC, Messonnier NE. Inching toward a serogroup B meningococcal vaccine for infants. JAMA 2012;307(6):614–5. [2] Joint Committee on Vaccination and Immunisation (JCVI) interim position statement on the use of Bexsero meningococcal B vaccine in the UK. Gov.UK. Department of Health, 24 July 2013. [3] Moxon R, Snape MD. The price of prevention: what now for immunisation against meningococcus B. Lancet 2013;382(9890):369–70. [4] Madhavan G, Sangha K, Phelps C, et al, Committee on Identifying and Prioritizing New Preventive Vaccines for Development, editors. Ranking vaccines: a prioritization software tool: phase II: prototype of a decision support system. Institute of Medicine, National Academies Press; 2013. p. 1–160. [5] Miller MA, Hinman AR. Economic analyses of vaccine policies. In: Plotkin SA, Orenstein WA, Offit PA, editors. Vaccines. 6th ed. Elsevier; 2013. p. 1413–26. [6] Hirth RA, Chernew ME, Miller E, Fendrick AM, Weissert WG. Willingness to pay for a quality-adjusted life year: in search of a standard. Med Decis Making 2000;20:332. [7] Ray GT, Whitney CG, Fireman BH, Ciuryla V, Black SB. Cost-effectiveness of pneumococcal conjugate vaccine evidence from the first 5 years of use in the United States incorporating herd effects. Pediatr Infect Dis 2006;25:494–501. [8] Miller MA, Sutter RW, Strebel PM, Hadler SC. Cost-effectiveness of incorporating inactivated poliovirus vaccine into the routine childhood immunization schedule. JAMA 1996;276(12):967–71. [9] Centers for Disease Control and Prevention: Vaccines for Children Program. VFC program distribution of pediatric vaccines. http://www.cdc.gov/ vaccines/programs/vfc/about/distribution.html [accessed 29.11.2013]. [10] Centers for Disease Control and Prevention (CDC). Serogroup A meningococcal conjugate vaccine coverage after the first national mass immunization campaign-Burkina Faso, 2011. MMWR Morb Mortal Wkly Rep 2012;61(50):1022–4. [11] Schwartz JL. Outbreaks, ethics and economics. Chronicle of Higher Education 2013, December 9.
D.S. Stephens ∗ R. Ahmed W.A. Orenstein Emory Vaccine Center, Emory University School of Medicine, United States ∗ Corresponding
author. Tel.: +1 404 727 8357; fax: +1 404 778 5434. E-mail address: [email protected] (D.S. Stephens) 30 September 2013 Available online 9 January 2014
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