Vaccine 32 (2014) 904–908
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
The introduction of new vaccines into developing countries. V: Will we lose a decade or more in the introduction of dengue vaccines to developing countries? Richard Mahoney ∗ Global Health Consultant, Sedona, AZ 86336, United States
a r t i c l e
i n f o
Article history: Received 6 November 2013 Received in revised form 11 December 2013 Accepted 18 December 2013 Available online 5 January 2014 Keywords: Dengue Vaccines Introduction Prelicensure
a b s t r a c t Dengue results in as many as 390 million infections annually and causes significant morbidity. A number of efforts are underway to develop vaccines against dengue. The public sector is undertaking efforts to create an enabling environment for vaccine introduction. Recent work by Brooks et al. provides a framework for analyzing which efforts should be undertaken before licensure. They conclude that actions before licensure are required to eliminate the decade or more it normally takes to introduce new vaccines into developing countries. We apply their methodology to dengue and identify a number of critical areas where public sector actions before licensure can greatly accelerate vaccine uptake. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction The burden of disease in developing countries is very large and there are many efforts underway to address this burden through the development and introduction of new health technologies. Time is of the essence for these efforts. Every day that is lost in the introduction of a new technology means that many people will needlessly suffer. In the case of dengue, every day of delay in full access of a dengue vaccine means that a minimum of 140,000 people will become infected and be at the risk of the severe morbidity of dengue. It is of greatest importance that delays in the introduction of new health technologies be minimized. In the mid-1990s Bill and Melinda Gates decided to establish a foundation of here-to-fore unheard size that would focus on technologies for improving health in developing countries. The foundation built on the experiences of the Population Council and PATH and began to generously fund a number of new public sector product development initiatives (known as Product Development Partnerships or PDPs) including several on vaccines including those concerned with HIV, malaria, TB, enteric, hookworm, meningitis, and eventually dengue vaccines. As experience was gained during the first decade of the 21st century with the operation of PDPs, a number of functions became accepted as necessary for PDP success. These included selective
∗ Tel.: +1 9283999255. E-mail addresses: [email protected], [email protected] 0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.12.061
support of preclinical studies, clinical studies through Phase III, and participation in obtaining National Regulatory Authority (NRA) licensure of new vaccines. A particular challenge has been to establish a clear framework for the work carried out by public sector groups to facilitate the introduction of new vaccines. An initial effort to propose a framework was made by Maynard and this author who identified five key elements in vaccine introduction based on work they had carried out in connection with hepatitis B vaccine [1]: (1) establishment and dissemination of disease burden data and of cost effectiveness computations, (2) vaccine introduction trials and effectiveness evaluations, (3) establishment of an international consensus on recommendations for vaccine use, (4) assurance of adequate and competitive vaccine supply, and (5) creation of funding mechanisms to supply vaccine to countries unable to finance their own procurement. This paper is the first of four addressing issues of introduction. The other address financing [2], intellectual property [3], and access policies in general [4]. The current paper, the fifth in the series, seeks to analyze access issues in more detail. Levine and colleagues proposed an introduction framework based on their work with pneumococcal vaccine, Haemophilus influenzae vaccine and rotavirus vaccine [5]. They proposed a framework with three groups of activities: Establish and organize evidence
• Disease burden assessments • Serotype epidemiology
R. Mahoney / Vaccine 32 (2014) 904–908
• Safety and efficacy determinations • Cost-effectiveness evaluations • Demand forecasts Establish support for global policies • Prepare vaccine recommendations • Establish financing policies • Mobilize procurement mechanisms Translate policies into local action • Develop political will to implement • Establish systems to deliver vaccine and monitor impact Both of these frameworks were proposed based on work that had been carried out with vaccines that had already received regulatory approval in one or more countries. The frameworks do not clearly lay out which activities can be undertaken before regulatory approval, which activities would be undertaken after regulatory approval, and which activities could be undertaken both before and after regulatory approval. More recently, the question has arisen as to the role of the public sector in facilitating the introduction of vaccines that have yet to receive regulatory approval. This question has more importance and possibly was previously unappreciated. Before a vaccine is licensed, there exists uncertainty as to whether the vaccine will be licensed. In particular, if a vaccine is in Phase III evaluation there is always the possibility that it may not prove to be sufficiently safe or effective to merit licensure. Such an outcome could lead to a delay of several years before a vaccine is licensed. What activities with respect to introduction can be undertaken and what level of resources do they deserve in the light of these uncertainties? Here we consider the example of dengue. Several vaccines are under development and it appears that one or more will be licensed within the next few years. What activities can and should be undertaken now, before regulatory approval, to shorten the length of time it will take to introduce the vaccines once they are licensed? 2. The role of the public sector in access A recent study by Brooks et al. [6] seeks to summarize our knowledge about what they refer to as access activities and to identify those that are most crucial before and after licensure. They analyze the time required to begin implementation for four vaccines and three malaria interventions. The vaccines were hepatitis B, H. influenzae type B, rotavirus and pneumococcal. The malaria interventions were insecticide treated mosquito nets, rapid diagnostic tests, and artemisinin-based combination therapy. The study concluded “A decade after each study vaccine or malaria intervention was approved by regulators, 33% or fewer lower and lower-middle income countries, and in most cases less than 15%, had begun to implement it. . .. The mean of the percentage of low income countries beginning implementation of each intervention after 5 years was 3% and 20% after 10 years. . .. No low income country implemented any of the new vaccines in the first 5 years.” Clearly such delays are unacceptable and every possible effort must be made to reduce these delays. The authors propose a new hypothesis concerning the implementation of new health technologies in developing countries. “The hypothesis suggests that organizations need to begin working systematically on access related issues earlier on, during the R&D stages, in order to shorten the time to begin implementation and realize equitable access in developing countries. Carefully paced activities during R&D could lead to decision-making processes at
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international and country levels and milestones being achieved shortly after regulatory approval. . ..” The analysis carried out by these authors presents a compelling case for the necessity of access related activities carried out through the R&D process and following licensure. The authors lay out a framework for activities that can be undertaken to accelerate implementation of new technologies before and after licensure (see Fig. 1). This represents a major contribution to our understanding of how to accelerate the introduction of new vaccines into developing countries. We have taken the framework and applied it to the situation with dengue vaccines as of 2013. 3. Access and dengue vaccines Dengue is a mosquito-borne disease of the tropics and subtropics caused by four related viruses DEN1–4. The human is the vertebrate host in the urban cycle. Dengue was prevalent at low levels in Asia up to the 1970s and was largely eliminated from the Americas by the early 1970s through vector control with DDT [7]. However, after the cessation of DDT use, the mosquitoes (Aedes aegypti, and, to a lesser extent, Aedes albopictus) made a resurgence and by now dengue has spread to virtually all of the tropical and sub-tropical areas and affects more than 125 countries and about half of the world’s population [8]. There are as many as 390 million infections per year [9]. All four viruses are prevalent in these areas. Vector control has proved of limited effectiveness in controlling dengue and there are no drugs. Clinical management of dengue cases can reduce the case fatality rate from about 20% to less than 1%. There is general agreement that the effective control of dengue will require the introduction of safe and effective vaccines. There are several dengue vaccines under development. Because of the global reach of all four viruses, a vaccine should be effective against all four. The most advanced is being developed by Sanofi Pasteur and is in Phase III studies [10]. Other vaccines being developed by GSK, Takeda, licensees of the U.S. NIH, Merck, and by the U.S. Navy are in Phase I and Phase II studies [11]. We estimate that several of these vaccines could be licensed in the coming years and that by 2020 there will be a variety of vaccines available for developing countries to use in their control of dengue (Table 1). Our estimates are based on publicly available information about the status of clinical development of each of the candidates. Here, we consider only those vaccines in Phase II or beyond. Using the current stage of development, we have applied the results of Davis et al. [12] with respect to the length of time that vaccines take to pass through each phase of development. They conclude that over the period 1995–2011, the minimum phase lengths for prophylactic vaccine was 2.91 years for Phase II and 2.10 years for Phase III. It is possible that the Phase III could begin before the end of Phase II, but these figures imply an approximate minimum of about 5 years from the launch of Phase II to the completion of Phase III. Based on interviews with 14 National Regulatory Agencies in Asia (unpublished data), we assume that licensure could occur in at least one country within the 12 months following completion of Phase III. This paper is based on our previous work with the Dengue Vaccine Initiative (DVI) which is a program of the International Vaccine Institute and has three partners: the International Vaccine
Table 1 Projected earliest licensure of dengue vaccines in Phase II or beyond. Developer
Phase of development
Projected earliest licensure
Butantan Institute Takeda Merck Sanofi Pasteur
II (begun in 2013) II (begun in 2012) II (begin in 2013) III (begun in 2011)
2018–2019 2017–2018 2018 2015
906
R. Mahoney / Vaccine 32 (2014) 904–908
Fig. 1. Proposed access framework incorporating R&D and implementation periods (after Brooks et al.).
Access Center at Johns Hopkins University, the Initiative for Vaccine Research at WHO, and the Sabin Vaccine Institute. Its goal is to develop an enabling environment for the accelerated introduction of dengue vaccines in developing countries. It undertakes two programs: Evidence for Decision Making, and Policy and Access. Within these programs it undertakes a wide-ranging set of activities including surveillance, capacity building in regulatory pathways, modeling of vaccine impact, development of introduction strategies, and economic analyses (see http://www.denguevaccines.org and http://www.denguevaccines.org/what-we-do). The programs as analyzed here were developed through a consultative process in which we played a role involving IVI and the three partners. Each of the partners has lead responsibilities (IVI: coordination, epidemiology, policy and access; IVAC: economics, financing, demand and supply; WHO: policy, regulatory, landscape analysis; Sabin: communications and advocacy) but most programs are conducted in a
collaborative manner with each partner contributing according to its skills and resources. These programs receive continuing funding from the Bill and Melinda Gates Foundation. If past approaches to vaccine introduction are used, it will be 2030 or later before a significant number of developing countries introduce and distribute dengue vaccines. What can be done to accelerate access? And, in particular, what can be done before licensure to accelerate access after licensure? Table 2 summarizes our application of the Brooks framework to dengue vaccines as of 2013. We deal only with actions that could be applied before licensure. We seek to identify those actions that could be undertaken and not dependent on the activities of the Dengue Vaccine Initiative (DVI), and those activities that would be dependent on DVI and its partners. For the DVI-dependent activities we seek to identify the value added and how the activities relate to the first licensed vaccine and to vaccines that would be licensed subsequent to the first vaccine.
R. Mahoney / Vaccine 32 (2014) 904–908
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Table 2 Pre-licensure actions and their relationship to first and subsequent licensure decision making. Actions
Work not dependent on DVI activities
Work dependent on DVI and partners
Activities
Value added
Relationship to first and subsequent licensures
Development of NIH vaccine candidate in GMP facility achieving prequalification Conduct of laboratory studies to assess dengue immunology in light of Sanofi Pasteur results. Search for surrogates of protection 1. Develop guidelines for diagnosis, clinical trials and production, and build capacity 2. Coordinate joint review of clinical trial applications by several NRAs
Assure sufficient supplies of safe, effective and affordable vaccine Provide valuable guidance to subsequent and later-generation vaccines
First: not essential Subsequent: essential
1. Essential for vaccine clinical trials, and for licensure, PQ, delivery standards, and pharmacovigilance 2. Accelerates speed through clinical trials
1. First: essential, subsequent: essential 2. First: not essential, subsequent: can greatly accelerate the application review process and reduce costs of application process First: will help countries understand limitations and opportunities of Sanofi Pasteur vaccine product profile Subsequent: will help guide mid-course corrections based on clinical trial results and scale up experience First: allows immediate decision making for vaccine supply following first licensure Subsequent: critical for capacity, marketing and distribution decisions First: facilitate decision making on capacity of core facility and potential use of additional production capacity Subsequent: facilitates decision making on production capacity First: not essential Subsequent: essential to expedite clinical development
Pre-clinical and clinical studies (Phases 1–3)
Execution of vaccine trials of lead candidate (Sanofi Pasteur) in numerous endemic countries
Regulatory oversight
NRAs respond on case-by-case basis to applications submitted by developers
Intervention design
Go no-go decisions on target product profile by developers
Assessment of target product profile for appropriateness to developing country requirements. WHO issued reports
Ensures that both developers and countries understand the rationale for product profiles and how the vaccines can best be used
Forecasting
Developer internal forecasts
Preparation of detailed global and country-specific strategic demand forecasts
Ensure that countries and donors understand the potentials and limiting factors for vaccine uptake
Manufacturing investment
Developer internal decisions
Strategic demand forecasting and financing evaluations
Assure sufficient supplies minimizing errors of over-confidence or under-estimates
R&D strategies to save costs
Developer internal decisions
These are generic studies that no individual company will address sufficiently
Preparation for financing strategies
Developer advocacy with individual governments
Laboratory research on questions concerning what determines vaccine efficacy and safety Consultations with national and international potential financers
Global decision planning
Developer advocacy with WHO and GAVI, etc.
WHO, SAGE, GAVI, and others assess priority and strategies for vaccine adoption and introduction
Ensure that WHO Guidelines, SAGE initial and full recommendations, and GAVI policies are in place at time of licensure
Clinical trial design
Developer internal decisions
Development of guidelines for second generation vaccines
National decision planning
Advocacy by developers
Preparation of national investment cases. Assessment of interaction of immunization and vector control
Provide guidance to companies, regulators, and developing country clinical investigators on the design of clinical trials including bridging studies for different age groups, etc. Ensure all information required for decision making is in place at time of vaccine availability
Burden of disease, economics, generating evidence of impact
Developer sponsored studies
National and global surveillance, burden of disease studies, cost of illness studies, willingness to pay studies, and model building. Advocacy and communications
Ensure that thorough review of all financing issues is completed as soon as possible
Build demand before vaccine licensure to reduce decision making delays thereafter
First: critical. allows immediate decision making following first licensure Subsequent: accelerates introduction and uptake First: essential: allows immediate decision making following first licensure Subsequent: essential. Accelerates introduction and uptake First: not essential Subsequent: essential for multiple vaccines
First: allows immediate decision making following first licensure Subsequent: accelerates introduction and uptake First: allows immediate decision making following first licensure Subsequent: ensures expanding and global demand to justify investment
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R. Mahoney / Vaccine 32 (2014) 904–908
Through this analysis we attempt to answer the question posed earlier, “What activities can and should be undertaken now, before regulatory approval, to shorten the length of time it will take to introduce the vaccines once they are licensed?” Those activities that contribute to the possible introduction of the lead candidate but also substantially contribute to planning for subsequent vaccines would seem to merit high priority. With respect to the potentially first-licensed vaccine, it can be seen that many of the activities carried out by DVI are important for the introduction of the vaccine. Most important is that the activities have the potential to greatly accelerate the introduction of dengue vaccines by allowing countries to make immediate decisions on the introduction of the vaccine following licensure rather than taking multiple years to evaluate a wide range of issues as has happened with other vaccines as analyzed by Brooks, et al. With respect to the subsequent licensed vaccines, it can be seen that the contributions of DVI are of perhaps greater importance. This is particularly true with respect to dengue because the product profile of the lead candidate is not ideal for use in developing countries. Administration of the Sanofi Pasteur live vaccine cannot begin until 2 years of age (although Sanofi Pasteur plans to do bridging studies that could bring the age of first administration down to 9 months) and the administration schedule is 0, 6, 12 months which does not correspond to any existing immunization schedule. It is possible that the Takeda and NIH vaccines will be effective with fewer doses. The GSK (inactivated vaccine) and the Merck (subunit vaccine) could be delivered in infancy in a schedule matching existing vaccines. Thus there are important public-sector reasons for accelerating the adoption of the subsequent vaccines. 4. Discussion During the first decade of the 21st century a number of PDPs, modeled on the Population Council and PATH, were established and began operation to accelerate the development and introduction of vaccines needed in developing countries. While it has always been agreed that these organizations could and should be involved in research and development, there was less consensus about the need for their involvement in introduction or “access” activities. And, in particular, there has been skepticism about the value of their work on access before a vaccine is licensed. Recent analyses, especially that of Brooks et al., have not only documented the importance of these access activities but have identified the key activities that need to be undertaken before licensure and are needed to accelerate the introduction of vaccines into developing countries and to reduce the very lengthy time it has taken for a number of other vaccines to be introduced, which is usually 10 years or more. The DVI is undertaking a wide range of activities consistent with the framework developed by Brooks et al. It can be expected that
these activities will result in a substantial reduction in the time delay for introduction of both first and second generation vaccines and thereby avoid needless morbidity and mortality, and the economic and social consequences of dengue. This analysis presents an application of a methodology for planning introduction strategies and implementation by the public sector and could be applied to other vaccine in development. Disclaimer The opinions expressed are those of the author and do not necessarily represent those of the DVI or the International Vaccine Institute. This paper is based on the work carried out by the DVI during the author’s tenure in that program which ended June 30, 2013. Acknowledgment This work has been supported by a grant from the Bill & Melinda Gates Foundation Grant No. 1016669. References [1] Mahoney R, Maynard JE. The introduction of new vaccines into developing countries. Vaccine 1999;17(7–8):646–52. [2] Mahoney R, Ramachandran S, Xu ZY. The introduction of new vaccines into developing countries. II. Vaccine financing. Vaccine 2000;18(24): 2625–35. [3] Mahoney RT, Pablos-Mendez A, Ramachandran S. The introduction of new vaccines into developing countries. III. The role of intellectual property. Vaccine 2004;22:786–92. [4] Mahoney RT, Krattiger A, Clemens JD, Curtiss 3rd R. The introduction of new vaccines into developing countries. IV. Global access strategies. Vaccine 2007;25(20):4003–11. [5] Levine OS, Hajjeh R, Wecker J, Cherian T, O’Brien KL, Knoll M, et al. A policy framework for accelerating adoption of new vaccines. Human Vaccines 2010;6(12):1021–4. [6] Brooks A, Smth TA, de Savigny D, Lengeler C. Implementing new health interventions in developing countries: why do we lose a decade or more? BMC Public Health 2012;12(683):17. [7] Gubler DJ, Kuno G, editors. Dengue and dengue hemorrhagic fever. Eastbourne, UK: CABI Publishing; 1997. [8] Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Neglected Tropical Diseases 2012;6(8):e1760. [9] Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature 2013;496(7446):504–7. [10] Sabchareon A, Wallace D, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. The Lancet 2012;380(9853):1559–67. [11] Murphy BR, Whitehead SS. Immune response to dengue virus and prospects for a vaccine. Annual Review of Immunology 2011;29:587–619. [12] Davis MM, Butchart AT, Wheeler JR, Coleman MS, Singer DC, Freed GL. Failureto-success ratios: transition probabilities and phase lengths for prophylactic vaccines versus other pharmaceuticals in the development pipeline. Vaccine 2011;29(51):9414–6.
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Review
The introduction of new vaccines into developing countries. V: Will we lose a decade or more in the introduction of dengue vaccines to developing countries? Richard Mahoney ∗ Global Health Consultant, Sedona, AZ 86336, United States
a r t i c l e
i n f o
Article history: Received 6 November 2013 Received in revised form 11 December 2013 Accepted 18 December 2013 Available online 5 January 2014 Keywords: Dengue Vaccines Introduction Prelicensure
a b s t r a c t Dengue results in as many as 390 million infections annually and causes significant morbidity. A number of efforts are underway to develop vaccines against dengue. The public sector is undertaking efforts to create an enabling environment for vaccine introduction. Recent work by Brooks et al. provides a framework for analyzing which efforts should be undertaken before licensure. They conclude that actions before licensure are required to eliminate the decade or more it normally takes to introduce new vaccines into developing countries. We apply their methodology to dengue and identify a number of critical areas where public sector actions before licensure can greatly accelerate vaccine uptake. © 2013 Elsevier Ltd. All rights reserved.
1. Introduction The burden of disease in developing countries is very large and there are many efforts underway to address this burden through the development and introduction of new health technologies. Time is of the essence for these efforts. Every day that is lost in the introduction of a new technology means that many people will needlessly suffer. In the case of dengue, every day of delay in full access of a dengue vaccine means that a minimum of 140,000 people will become infected and be at the risk of the severe morbidity of dengue. It is of greatest importance that delays in the introduction of new health technologies be minimized. In the mid-1990s Bill and Melinda Gates decided to establish a foundation of here-to-fore unheard size that would focus on technologies for improving health in developing countries. The foundation built on the experiences of the Population Council and PATH and began to generously fund a number of new public sector product development initiatives (known as Product Development Partnerships or PDPs) including several on vaccines including those concerned with HIV, malaria, TB, enteric, hookworm, meningitis, and eventually dengue vaccines. As experience was gained during the first decade of the 21st century with the operation of PDPs, a number of functions became accepted as necessary for PDP success. These included selective
∗ Tel.: +1 9283999255. E-mail addresses: [email protected], [email protected] 0264-410X/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.vaccine.2013.12.061
support of preclinical studies, clinical studies through Phase III, and participation in obtaining National Regulatory Authority (NRA) licensure of new vaccines. A particular challenge has been to establish a clear framework for the work carried out by public sector groups to facilitate the introduction of new vaccines. An initial effort to propose a framework was made by Maynard and this author who identified five key elements in vaccine introduction based on work they had carried out in connection with hepatitis B vaccine [1]: (1) establishment and dissemination of disease burden data and of cost effectiveness computations, (2) vaccine introduction trials and effectiveness evaluations, (3) establishment of an international consensus on recommendations for vaccine use, (4) assurance of adequate and competitive vaccine supply, and (5) creation of funding mechanisms to supply vaccine to countries unable to finance their own procurement. This paper is the first of four addressing issues of introduction. The other address financing [2], intellectual property [3], and access policies in general [4]. The current paper, the fifth in the series, seeks to analyze access issues in more detail. Levine and colleagues proposed an introduction framework based on their work with pneumococcal vaccine, Haemophilus influenzae vaccine and rotavirus vaccine [5]. They proposed a framework with three groups of activities: Establish and organize evidence
• Disease burden assessments • Serotype epidemiology
R. Mahoney / Vaccine 32 (2014) 904–908
• Safety and efficacy determinations • Cost-effectiveness evaluations • Demand forecasts Establish support for global policies • Prepare vaccine recommendations • Establish financing policies • Mobilize procurement mechanisms Translate policies into local action • Develop political will to implement • Establish systems to deliver vaccine and monitor impact Both of these frameworks were proposed based on work that had been carried out with vaccines that had already received regulatory approval in one or more countries. The frameworks do not clearly lay out which activities can be undertaken before regulatory approval, which activities would be undertaken after regulatory approval, and which activities could be undertaken both before and after regulatory approval. More recently, the question has arisen as to the role of the public sector in facilitating the introduction of vaccines that have yet to receive regulatory approval. This question has more importance and possibly was previously unappreciated. Before a vaccine is licensed, there exists uncertainty as to whether the vaccine will be licensed. In particular, if a vaccine is in Phase III evaluation there is always the possibility that it may not prove to be sufficiently safe or effective to merit licensure. Such an outcome could lead to a delay of several years before a vaccine is licensed. What activities with respect to introduction can be undertaken and what level of resources do they deserve in the light of these uncertainties? Here we consider the example of dengue. Several vaccines are under development and it appears that one or more will be licensed within the next few years. What activities can and should be undertaken now, before regulatory approval, to shorten the length of time it will take to introduce the vaccines once they are licensed? 2. The role of the public sector in access A recent study by Brooks et al. [6] seeks to summarize our knowledge about what they refer to as access activities and to identify those that are most crucial before and after licensure. They analyze the time required to begin implementation for four vaccines and three malaria interventions. The vaccines were hepatitis B, H. influenzae type B, rotavirus and pneumococcal. The malaria interventions were insecticide treated mosquito nets, rapid diagnostic tests, and artemisinin-based combination therapy. The study concluded “A decade after each study vaccine or malaria intervention was approved by regulators, 33% or fewer lower and lower-middle income countries, and in most cases less than 15%, had begun to implement it. . .. The mean of the percentage of low income countries beginning implementation of each intervention after 5 years was 3% and 20% after 10 years. . .. No low income country implemented any of the new vaccines in the first 5 years.” Clearly such delays are unacceptable and every possible effort must be made to reduce these delays. The authors propose a new hypothesis concerning the implementation of new health technologies in developing countries. “The hypothesis suggests that organizations need to begin working systematically on access related issues earlier on, during the R&D stages, in order to shorten the time to begin implementation and realize equitable access in developing countries. Carefully paced activities during R&D could lead to decision-making processes at
905
international and country levels and milestones being achieved shortly after regulatory approval. . ..” The analysis carried out by these authors presents a compelling case for the necessity of access related activities carried out through the R&D process and following licensure. The authors lay out a framework for activities that can be undertaken to accelerate implementation of new technologies before and after licensure (see Fig. 1). This represents a major contribution to our understanding of how to accelerate the introduction of new vaccines into developing countries. We have taken the framework and applied it to the situation with dengue vaccines as of 2013. 3. Access and dengue vaccines Dengue is a mosquito-borne disease of the tropics and subtropics caused by four related viruses DEN1–4. The human is the vertebrate host in the urban cycle. Dengue was prevalent at low levels in Asia up to the 1970s and was largely eliminated from the Americas by the early 1970s through vector control with DDT [7]. However, after the cessation of DDT use, the mosquitoes (Aedes aegypti, and, to a lesser extent, Aedes albopictus) made a resurgence and by now dengue has spread to virtually all of the tropical and sub-tropical areas and affects more than 125 countries and about half of the world’s population [8]. There are as many as 390 million infections per year [9]. All four viruses are prevalent in these areas. Vector control has proved of limited effectiveness in controlling dengue and there are no drugs. Clinical management of dengue cases can reduce the case fatality rate from about 20% to less than 1%. There is general agreement that the effective control of dengue will require the introduction of safe and effective vaccines. There are several dengue vaccines under development. Because of the global reach of all four viruses, a vaccine should be effective against all four. The most advanced is being developed by Sanofi Pasteur and is in Phase III studies [10]. Other vaccines being developed by GSK, Takeda, licensees of the U.S. NIH, Merck, and by the U.S. Navy are in Phase I and Phase II studies [11]. We estimate that several of these vaccines could be licensed in the coming years and that by 2020 there will be a variety of vaccines available for developing countries to use in their control of dengue (Table 1). Our estimates are based on publicly available information about the status of clinical development of each of the candidates. Here, we consider only those vaccines in Phase II or beyond. Using the current stage of development, we have applied the results of Davis et al. [12] with respect to the length of time that vaccines take to pass through each phase of development. They conclude that over the period 1995–2011, the minimum phase lengths for prophylactic vaccine was 2.91 years for Phase II and 2.10 years for Phase III. It is possible that the Phase III could begin before the end of Phase II, but these figures imply an approximate minimum of about 5 years from the launch of Phase II to the completion of Phase III. Based on interviews with 14 National Regulatory Agencies in Asia (unpublished data), we assume that licensure could occur in at least one country within the 12 months following completion of Phase III. This paper is based on our previous work with the Dengue Vaccine Initiative (DVI) which is a program of the International Vaccine Institute and has three partners: the International Vaccine
Table 1 Projected earliest licensure of dengue vaccines in Phase II or beyond. Developer
Phase of development
Projected earliest licensure
Butantan Institute Takeda Merck Sanofi Pasteur
II (begun in 2013) II (begun in 2012) II (begin in 2013) III (begun in 2011)
2018–2019 2017–2018 2018 2015
906
R. Mahoney / Vaccine 32 (2014) 904–908
Fig. 1. Proposed access framework incorporating R&D and implementation periods (after Brooks et al.).
Access Center at Johns Hopkins University, the Initiative for Vaccine Research at WHO, and the Sabin Vaccine Institute. Its goal is to develop an enabling environment for the accelerated introduction of dengue vaccines in developing countries. It undertakes two programs: Evidence for Decision Making, and Policy and Access. Within these programs it undertakes a wide-ranging set of activities including surveillance, capacity building in regulatory pathways, modeling of vaccine impact, development of introduction strategies, and economic analyses (see http://www.denguevaccines.org and http://www.denguevaccines.org/what-we-do). The programs as analyzed here were developed through a consultative process in which we played a role involving IVI and the three partners. Each of the partners has lead responsibilities (IVI: coordination, epidemiology, policy and access; IVAC: economics, financing, demand and supply; WHO: policy, regulatory, landscape analysis; Sabin: communications and advocacy) but most programs are conducted in a
collaborative manner with each partner contributing according to its skills and resources. These programs receive continuing funding from the Bill and Melinda Gates Foundation. If past approaches to vaccine introduction are used, it will be 2030 or later before a significant number of developing countries introduce and distribute dengue vaccines. What can be done to accelerate access? And, in particular, what can be done before licensure to accelerate access after licensure? Table 2 summarizes our application of the Brooks framework to dengue vaccines as of 2013. We deal only with actions that could be applied before licensure. We seek to identify those actions that could be undertaken and not dependent on the activities of the Dengue Vaccine Initiative (DVI), and those activities that would be dependent on DVI and its partners. For the DVI-dependent activities we seek to identify the value added and how the activities relate to the first licensed vaccine and to vaccines that would be licensed subsequent to the first vaccine.
R. Mahoney / Vaccine 32 (2014) 904–908
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Table 2 Pre-licensure actions and their relationship to first and subsequent licensure decision making. Actions
Work not dependent on DVI activities
Work dependent on DVI and partners
Activities
Value added
Relationship to first and subsequent licensures
Development of NIH vaccine candidate in GMP facility achieving prequalification Conduct of laboratory studies to assess dengue immunology in light of Sanofi Pasteur results. Search for surrogates of protection 1. Develop guidelines for diagnosis, clinical trials and production, and build capacity 2. Coordinate joint review of clinical trial applications by several NRAs
Assure sufficient supplies of safe, effective and affordable vaccine Provide valuable guidance to subsequent and later-generation vaccines
First: not essential Subsequent: essential
1. Essential for vaccine clinical trials, and for licensure, PQ, delivery standards, and pharmacovigilance 2. Accelerates speed through clinical trials
1. First: essential, subsequent: essential 2. First: not essential, subsequent: can greatly accelerate the application review process and reduce costs of application process First: will help countries understand limitations and opportunities of Sanofi Pasteur vaccine product profile Subsequent: will help guide mid-course corrections based on clinical trial results and scale up experience First: allows immediate decision making for vaccine supply following first licensure Subsequent: critical for capacity, marketing and distribution decisions First: facilitate decision making on capacity of core facility and potential use of additional production capacity Subsequent: facilitates decision making on production capacity First: not essential Subsequent: essential to expedite clinical development
Pre-clinical and clinical studies (Phases 1–3)
Execution of vaccine trials of lead candidate (Sanofi Pasteur) in numerous endemic countries
Regulatory oversight
NRAs respond on case-by-case basis to applications submitted by developers
Intervention design
Go no-go decisions on target product profile by developers
Assessment of target product profile for appropriateness to developing country requirements. WHO issued reports
Ensures that both developers and countries understand the rationale for product profiles and how the vaccines can best be used
Forecasting
Developer internal forecasts
Preparation of detailed global and country-specific strategic demand forecasts
Ensure that countries and donors understand the potentials and limiting factors for vaccine uptake
Manufacturing investment
Developer internal decisions
Strategic demand forecasting and financing evaluations
Assure sufficient supplies minimizing errors of over-confidence or under-estimates
R&D strategies to save costs
Developer internal decisions
These are generic studies that no individual company will address sufficiently
Preparation for financing strategies
Developer advocacy with individual governments
Laboratory research on questions concerning what determines vaccine efficacy and safety Consultations with national and international potential financers
Global decision planning
Developer advocacy with WHO and GAVI, etc.
WHO, SAGE, GAVI, and others assess priority and strategies for vaccine adoption and introduction
Ensure that WHO Guidelines, SAGE initial and full recommendations, and GAVI policies are in place at time of licensure
Clinical trial design
Developer internal decisions
Development of guidelines for second generation vaccines
National decision planning
Advocacy by developers
Preparation of national investment cases. Assessment of interaction of immunization and vector control
Provide guidance to companies, regulators, and developing country clinical investigators on the design of clinical trials including bridging studies for different age groups, etc. Ensure all information required for decision making is in place at time of vaccine availability
Burden of disease, economics, generating evidence of impact
Developer sponsored studies
National and global surveillance, burden of disease studies, cost of illness studies, willingness to pay studies, and model building. Advocacy and communications
Ensure that thorough review of all financing issues is completed as soon as possible
Build demand before vaccine licensure to reduce decision making delays thereafter
First: critical. allows immediate decision making following first licensure Subsequent: accelerates introduction and uptake First: essential: allows immediate decision making following first licensure Subsequent: essential. Accelerates introduction and uptake First: not essential Subsequent: essential for multiple vaccines
First: allows immediate decision making following first licensure Subsequent: accelerates introduction and uptake First: allows immediate decision making following first licensure Subsequent: ensures expanding and global demand to justify investment
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Through this analysis we attempt to answer the question posed earlier, “What activities can and should be undertaken now, before regulatory approval, to shorten the length of time it will take to introduce the vaccines once they are licensed?” Those activities that contribute to the possible introduction of the lead candidate but also substantially contribute to planning for subsequent vaccines would seem to merit high priority. With respect to the potentially first-licensed vaccine, it can be seen that many of the activities carried out by DVI are important for the introduction of the vaccine. Most important is that the activities have the potential to greatly accelerate the introduction of dengue vaccines by allowing countries to make immediate decisions on the introduction of the vaccine following licensure rather than taking multiple years to evaluate a wide range of issues as has happened with other vaccines as analyzed by Brooks, et al. With respect to the subsequent licensed vaccines, it can be seen that the contributions of DVI are of perhaps greater importance. This is particularly true with respect to dengue because the product profile of the lead candidate is not ideal for use in developing countries. Administration of the Sanofi Pasteur live vaccine cannot begin until 2 years of age (although Sanofi Pasteur plans to do bridging studies that could bring the age of first administration down to 9 months) and the administration schedule is 0, 6, 12 months which does not correspond to any existing immunization schedule. It is possible that the Takeda and NIH vaccines will be effective with fewer doses. The GSK (inactivated vaccine) and the Merck (subunit vaccine) could be delivered in infancy in a schedule matching existing vaccines. Thus there are important public-sector reasons for accelerating the adoption of the subsequent vaccines. 4. Discussion During the first decade of the 21st century a number of PDPs, modeled on the Population Council and PATH, were established and began operation to accelerate the development and introduction of vaccines needed in developing countries. While it has always been agreed that these organizations could and should be involved in research and development, there was less consensus about the need for their involvement in introduction or “access” activities. And, in particular, there has been skepticism about the value of their work on access before a vaccine is licensed. Recent analyses, especially that of Brooks et al., have not only documented the importance of these access activities but have identified the key activities that need to be undertaken before licensure and are needed to accelerate the introduction of vaccines into developing countries and to reduce the very lengthy time it has taken for a number of other vaccines to be introduced, which is usually 10 years or more. The DVI is undertaking a wide range of activities consistent with the framework developed by Brooks et al. It can be expected that
these activities will result in a substantial reduction in the time delay for introduction of both first and second generation vaccines and thereby avoid needless morbidity and mortality, and the economic and social consequences of dengue. This analysis presents an application of a methodology for planning introduction strategies and implementation by the public sector and could be applied to other vaccine in development. Disclaimer The opinions expressed are those of the author and do not necessarily represent those of the DVI or the International Vaccine Institute. This paper is based on the work carried out by the DVI during the author’s tenure in that program which ended June 30, 2013. Acknowledgment This work has been supported by a grant from the Bill & Melinda Gates Foundation Grant No. 1016669. References [1] Mahoney R, Maynard JE. The introduction of new vaccines into developing countries. Vaccine 1999;17(7–8):646–52. [2] Mahoney R, Ramachandran S, Xu ZY. The introduction of new vaccines into developing countries. II. Vaccine financing. Vaccine 2000;18(24): 2625–35. [3] Mahoney RT, Pablos-Mendez A, Ramachandran S. The introduction of new vaccines into developing countries. III. The role of intellectual property. Vaccine 2004;22:786–92. [4] Mahoney RT, Krattiger A, Clemens JD, Curtiss 3rd R. The introduction of new vaccines into developing countries. IV. Global access strategies. Vaccine 2007;25(20):4003–11. [5] Levine OS, Hajjeh R, Wecker J, Cherian T, O’Brien KL, Knoll M, et al. A policy framework for accelerating adoption of new vaccines. Human Vaccines 2010;6(12):1021–4. [6] Brooks A, Smth TA, de Savigny D, Lengeler C. Implementing new health interventions in developing countries: why do we lose a decade or more? BMC Public Health 2012;12(683):17. [7] Gubler DJ, Kuno G, editors. Dengue and dengue hemorrhagic fever. Eastbourne, UK: CABI Publishing; 1997. [8] Brady OJ, Gething PW, Bhatt S, Messina JP, Brownstein JS, Hoen AG, et al. Refining the global spatial limits of dengue virus transmission by evidence-based consensus. PLoS Neglected Tropical Diseases 2012;6(8):e1760. [9] Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, et al. The global distribution and burden of dengue. Nature 2013;496(7446):504–7. [10] Sabchareon A, Wallace D, Sirivichayakul C, Limkittikul K, Chanthavanich P, Suvannadabba S, et al. Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial. The Lancet 2012;380(9853):1559–67. [11] Murphy BR, Whitehead SS. Immune response to dengue virus and prospects for a vaccine. Annual Review of Immunology 2011;29:587–619. [12] Davis MM, Butchart AT, Wheeler JR, Coleman MS, Singer DC, Freed GL. Failureto-success ratios: transition probabilities and phase lengths for prophylactic vaccines versus other pharmaceuticals in the development pipeline. Vaccine 2011;29(51):9414–6.
