Meeting Report - Malaria Vaccine Initiative

Identify the types of economic and market information needed to: Make the case for investment in malaria vaccine development. Address policy issues. Enter into planning for vaccine introduction.Identify the gaps in economic and market data needed to inform future investment decisions.Outline a coordinated research agenda to address the identified information gaps.The meeting organizers saw this meeting as a first step toward future discussion andcollaboration among private and public sector groups interested in undertaking studies needed toprovide better information for policy- and decision-makers as a way to improve the investmentenvironment for malaria vaccine development and to lay the groundwork for the futureintroduction of malaria vaccines.Summary of Presentations & Group DiscussionsThe Malaria Vaccine Market Consultation combined formal presentations by public and privatesector experts in the field of vaccine development with group discussion to achieve itsobjectives. Presentations on the first day introduced key issues that would be discussedthroughout the meeting:market assessment/analysis;pharmaco-economic studies;demand forecasting;case studies based on how those developing other vaccines have proceeded;needs and uses of economic data; andreview of relevant methodologies.Additionally, participants representing various disciplines shared their perspectives on the needfor and uses of market and pharmaco-economic data. These perspectives formed the basis fordiscussions on research gaps.The following meeting notes are organized by topic and reflect both individual presentations andrelated discussions. The meeting agenda is included as Appendix 1, a list of meeting participantsis provided in Appendix 2, and Appendix 3 lists acronyms used in this report.I. Market Information/Market Analysis: What Does It Mean?Market studies and analyses are necessary in order to answer a broad spectrum of questions and,ultimately, “what should we do?”. Dr. Thierry Darcis of GlaxoSmithKline Biologicals (GSK)explained that his company applies a widely accepted framework, AIDA (Awareness, Interest,Demand, and Adoption), for understanding the market.AIDA should be utilized to understand potential barriers to malaria vaccine introduction and use,then to try to quantify the percent of the uptake (the number of doses actually used), and finally2

to develop an action plan. Based on an analysis of the results of three exploratory qualitativeresearch studies conducted in three African countries, GSK has useful data on all four aspects ofAIDA for malaria vaccines:Awareness:There is no need to spend time or money raising awareness about malaria. Awareness was veryhigh among all stakeholders—from mothers to policy makers.Interest: There is already a high level of interest in malaria vaccines, because malaria is considered ahigh cost disease that is potentially fatal and impacts disproportionately on the poor. All groups recognized the limited efficacy of current methods of prevention andacknowledged that compliance is often poor. For example, the high cost of medication meansthat pregnant women often take only half the recommended dosage. Doctors acknowledge that malaria drug resistance is increasing. There is a strong perception that prevention should be financed by government. Whiletherapy is seen as an individual’s problem, prophylaxis is seen as the government’sresponsibility.Demand: Participants believe that all vaccines are very safe and effective, so expectations for a malariavaccine are high. Vaccine should not be used first on adults (GSK’s original plan). Product profile must makeinfants, young children, and pregnant women its highest priorities. When efficacy falls below 70%, and when too many and too frequent boosters are required,participants lose interest. In the absence of a licensed malaria vaccine, bed nets are being used for prevention. Withinthe next few years, two questions must be answered: Can we—or should we—position thevaccine so that it is seen as a complementary technology? If so, is there added value inpromoting a combination of the two?Adoption: Consumers expect vaccines to be either free or heavily subsidized by the government. Systems for vaccine distribution are already in place.An action plan for GSK, based on what has been learned thus far, should include the following: Conduct research in rural areas to broaden understanding of the population. Collect more information on barriers to adoption. Ensure at least a minimally acceptable product profile. Learn more about the value of a lowerefficacy vaccine—say 30% and ways to communicate this to the population. Conduct quantitative research after more information is available on the product profile, andthe various values it can deliver. Make sure the vaccine can fit within the Expanded Programme on Immunization (EPI)system, which is currently perceived as the only distribution system.3

When a vaccine profile and financing systems are in place, quantify how refinements to thesecan lead to greater demand.II. Introducing New Vaccines: Issues for Pharmaco-economic EvaluationThe purpose of economic evaluation is to determine if available resources are being used toproduce the maximum effect at minimum cost. Julia Fox-Rushby, from the London School ofHygiene and Tropical Medicine, explained that there are only two requirements for a fulleconomic evaluation:Both costs and effects (or benefits) are included.The intervention is compared to alternative(s).There are three main types of economic evaluation: cost-effectiveness analysis (CEA), costutility analysis (CUA), and cost/benefit analysis (CBA). All are measured in terms of money.1. CEA examines an effect of interest to both of the other types of analysis: for example, thenumber of children immunized using two alternate approaches. But CEA can only look atone effect at a time and thus produces only one effectiveness ratio. Because interventionshave many different effects, many cost-effectiveness (C/E) ratios are needed.2. CUA is a method of incorporating multiple effects e.g., morbidity and mortality together,using composite indicators such as quality adjusted life years (QALY) and disability adjustedlife years (DALY).3. CBA uses single or multiple effects that may or may not be common to the alternatives. CBAis the only type of evaluation that can give a monetary value to a range of different effectsthat might result from an intervention.It is important to know who needs to make decisions, what types of decisions need to be made,and for what purpose. This is because in any economic evaluation the alternatives chosen forcomparison have an important bearing on the results of the analysis. Thus, the ultimate decisionmakersshould be identified before undertaking pharmaco-economic studies.Measuring costs in economic analysis: Evaluators are interested in the economic costs of allthe resources used to run a program, measuring them, and then valuing them. Finding the total,average, and marginal cost for each alternative tells how costs change with production.Measuring incremental costs, such as the additional costs of the malaria vaccine over and abovethe alternative to which it is compared, will help determine what is and is not cost effective.It is difficult to transfer the results of cost-effectiveness studies across countries because thestudies often use different indicators and measures of effectiveness. There is also very little datathat would enable someone to compare the C/E of a malaria vaccine to other vaccines on themarket.Measuring effects in economic analysis: Effects are dependent upon the type of comparisonand the type of decision(s) being made. For example, a study measuring the cost of deaths4

averted by introducing a vaccine often tells the decision-maker nothing about the adverse eventsthat might be associated with using that vaccine or their cost. Evaluators note that the source,quality, and specificity of available data are often unknown. Thus, even when the disease burdenis known, it cannot be said what amount of that burden can be prevented by use of a vaccine.Measuring benefits: The difference between demand and willingness to pay (WTP) as measuresof social development is particularly important for vaccines because vaccines are considered apublic good. If evaluators look only at a market demand curve, they will probably underestimatethe benefit of using the vaccine, because the public good of disease reduction resulting fromlower disease transmission will remain unaccounted for. Therefore, WTP is a good measure ofbenefits only if WTP studies are carefully designed to capture the additional estimate of benefitsfor an entire population.Linking costs and effects: Cost and effect information should be used for the same populations,but that seldom happens. There is very little good data based on the same populations. Instead,modeling often draws local cost data from one setting and information on effectiveness fromvarious other settings. Dr. Fox-Rushby proposes that in the early stages of future clinical trialsresearchers consider building in “some of the economics.” With more information on variationsin cost (e.g., if prevalence rates decrease over time, what impact does this have on costs overtime?), the testing of assumptions will be more relevant for decision-makers.What is known from pharmaco-economic evaluations to date: The types of vaccine and the schedule have a major impact on the C/E ratio. Thus, the bestapproach is to fit any new vaccine delivery into an existing vaccine schedule/program. If, in the future, we increase coverage of malaria vaccine, this will have an impact on the useof other vaccines and could be seen as a benefit of providing the malaria vaccine. More information is needed—from different settings—on the impact of using monovalent vs.combination vaccines, and on the size of vials. In addition to the need for global analysis,differences in specific settings need to be examined, as decisions are taken locally. There is more economic data on malaria than on other tropical diseases because of numerousbed net trials.Currently, economic evaluations provide little information about sustainability.5

III. HIV/AIDS Vaccine Need ForecastYvette Madrid, consultant to the International AIDS Vaccine Initiative (IAVI), reported on aWorld Health Organization (WHO)/Joint United Nations Program on HIV/AIDS (UNAIDS) andIAVI collaborative study designed to estimate global HIV/AIDS vaccine needs from a publichealth perspective. Study methodology and results were presented as a model of what othergroups, also interested in learning more about the introduction of new vaccines into developingcountries, have done to estimate needs and initiate discussions with policy-makers. The researchdid not examine cost implications.Researchers developed an HIV/AIDS vaccine profile that assumed: efficacy of 30% and 90%(mixed prevention and modification of infection); effective against prevalent strains;intramuscular with three shots in the first year and a booster every five years; safe for use ininfected individuals but with no therapeutic benefits; and no significant side effects. Furtherassumptions were that demand would be driven by public policy; the vaccine would be free toend-users with delivery costs and any new infrastructure assumed by each country; and allcountries would adopt at the same time (2001).Four focus group discussions (FGDs) in Latin America, Asia, sub-Saharan Africa, and theindustrialized world were conducted with representatives from public health sector programs andNGOs. All had backgrounds in immunization and/or HIV/AIDS. During the discussions theywere asked their opinions as to which populations they would like to target; what proportion ofthe population could be reached with existing services; and what proportion of “need” wouldagree to the full vaccination schedule.From these discussions, researchers learned among other things that if the low-efficacy vaccineis used, participants believed that they would be able to reach less than 20% of those needing thevaccine. If the high efficacy vaccine were available, it would be easier to reach more people withthe full regimen. Still, only 36% of those in need would be reached.Following initial reviews of these FGD findings, a follow-up consultation was held forrepresentatives from industry and the participating countries. An epidemiologist presentedinformation on epidemiological models and the impact that an HIV/AIDS vaccine would have indifferent situations.The following conclusions—many of which have implications for malaria vaccines—are basedon both the study and the consultation:Overall policy objectives should have been determined before FGD participants were askedto look at various immunization strategies. Different objectives would lead to differentdecisions and strategies as to who should be immunized.Future researchers should give people an understanding of what various vaccine profilesactually mean before delving into the policy implications.Participants had little understanding of what can be achieved with a “low” efficacy vaccineor a vaccine with different efficacy profiles. People do not understand the implications ofdifferent forms of efficacy and how efficacy relates to impact. However, it is important to6

note that during the consultation, participants gained insights into the concept that a lowefficacy vaccine could lower transmission of infection, and that this could be quite useful.The advantages of universal immunization policies were not adequately explored.Participants were concerned about the effects of stigma when targeting high-risk groups.The public sector needs to determine how it can close the gap between what it could nowdeliver and what it would need to deliver.This study assumed universal simultaneous vaccine adoption into existing and neededdelivery capacity. While this is an appealing strategy, it is neither realistic nor practical.There remains a large gap between the credibility of projections and historical experience. Ifcountries have to make decisions based on one or the other, they will follow the latter. Theresearchers’ challenge is to align public sector programmatic assumptions with realisticexpectations.Traditionally, it was believed that any new vaccine would be introduced within a “leveraged”model—i.e., there is a reasonable market in volume and sales in industrial countries and alarge (in volume) but limited market (in sales) in less developed countries. At the other endof the spectrum, is the “orphan” model, where the demand and volume are primarily fromless developed countries, and very little revenue comes from industrialized markets. A lowefficacy HIV/AIDS vaccine probably falls within the “leveraged” market; but this will not beknown until after Phase 3 clinical trials are completed. This adds a degree of risk, not only tothose producing the product, but also to those who are trying to promote access.There is still much to learn about delivery systems, especially what types of deliverymechanisms will best reach adults.Finally, a forecast is not definitive; many things change with time. Studies similar to this one willneed to be repeated as more information is gathered.IV. Malaria Vaccines: 2001 Market AssessmentMVI commissioned Lisa Barnard to review existing research data to assess the potential globalmarket for malaria vaccines and identify gaps in the data. The draft report surveys marketinformation and identifies gaps in market data. Its purpose is to determine what types ofinformation gathering should be funded so that existing gaps can be replaced with knowledge.Although malaria threatens approximately 2.3 billion persons per year, investment in vaccineresearch and development is low compared to need, in part because malaria is perceived as adisease of poor countries where citizens are unable to pay for medicines, and because there is alack of adequate infrastructure to deliver the vaccines. Ms. Barnard argued that a sizable andreliable market, in fact, exists.The global market can be segmented into developed-world and developing-world categories. Inthe developed world, the market could include business and leisure travelers, the military, andthose from industrialized countries who reside temporarily in developing countries. In thedeveloping world, malaria is endemic in most tropical and semi-tropical areas and causes anestimated 2.7 million deaths each year.7

Travelers’ Market: A 1999 market report, based on yellow fever vaccine sales trends indeveloped countries, predicted that if a malaria vaccine were marketed in 2004, revenues fromtravelers using the vaccine would be $240 million in 2005, with a market growth rate of 47%.However, while world travel to exotic locations has increased dramatically in recent years,2001’s economic and political events have led to a downturn in business and pleasure travel.Thus, there are uncertainties as to the future size of a travelers’ market. Among factors such asthe cost of a vaccine vs. the cost of an existing drug prophylaxis, the vaccine market dependsupon the number of vacationers traveling to developing countries, business decisions regardingcontinued or future investments abroad, and the operating budgets of NGOs and bilateral andmultilateral organizations working in the developing world.The introduction of other travel vaccines should positively influence a potential travelers’market; new protective products create a “cluster” effect, making a trip to the travel clinic moreworthwhile. Furthermore, each product introduction (e.g., hepatitis A vaccine) and advertisingeffort promotes awareness, cultural habits of going to a travel clinic, and appreciation for thebenefits of vaccines.Military Market: Since malaria is the top naturally-occurring threat to the military and hasalready caused serious morbidity and mortality during wartime and peacekeeping operations, themilitary represents the most stable market segment with the most predictable number of dosesrequired. Many militaries have already indicated the number of personnel they would vaccinateto prevent malaria. Military requirements worldwide would approach a minimum market of500,000 persons initially, and 75,000 annually thereafter.An estimate of revenues from a vaccine for military personnel in the United States (US), UnitedKingdom (UK), and Canada during the first year is $25 million, with $3.7 million each yearthereafter (based on $50 per person/course for 500,000 persons initially, 75,000 thereafter).When other countries such as Australia, India, and China are included, an additional $34 millionin sales is possible in the first year, with another $5 million a year in subsequent years (based on1.7 million persons at $20 per person/course in the first year, 255,000 persons thereafter).Developing-World Market: Developing countries suffer greatly from the effects of malaria, andtheir governments are beginning to understand the many ways this disease burden adverselyaffects their economies. This is the largest segment of a potential malaria vaccine market, as theneed is enormous, but large knowledge gaps exist, including the nature of the demand, the targetpopulation, willingness and ability to pay for the vaccine, and the feasibility and cost of gettingthe vaccines to those in need. Theoretically, there is a significant enough market to rewardprivate sector vaccine developers. But this will require new sources of funds from donoragencies for vaccine purchase and immunization programs. Guaranteeing a market is morecomplex than existing international health agencies such as the United Nations Children’s Fund(UNICEF), WHO, and the World Bank can manage with their current structures and/orresources.While a vaccine with efficacy against only the P. falciparum strain of malaria would beacceptable to African markets, a vaccine against both P. falciparum and P. vivax might berequired for acceptance in the remainder of the world. Huge potential markets exist in Asia and8

South America, but current gaps in knowledge include: the size of the private market, how muchpopulations in Asia and South America will value the vaccine, and how political environmentswill affect sales.In terms of market numbers, if 30% of the at-risk population in countries affected primarily by P.vivax were immunized, this would equal 261 million people. If coverage reached 50%, 434million people would be immunized. In Africa, if 30% of the at-risk population for P. falciparummalaria were immunized, this would equal 340 million people. If a combination falciparumvivaxvaccine were developed, coverage of 30% would mean that 1.2 billion people were beingimmunized.Conclusions: The public health need for a vaccine is strong. Need and demand are similar for travelers. Need and demand diverge for developing countries. More information about the size of private markets, WTP, and government commitments isneeded to strengthen the argument that a sizable market for a malaria vaccine currentlyexists.V. Industry Analysis of Market DemandGSK forecasts all its products in a very similar, systematic way. Dr. Thierry Darcis shared one ofthe tables GSK uses to forecast malaria vaccine volume. In appearance it is a simple outputspreadsheet, but many computations are used to arrive at the final figures. The results enableGSK’s new product developers to look at the projected market in terms of tenders, market share(both GSK and potential competitors), and required doses. It shows a peak volume for sub-Saharan Africa (SSA) of 110,000,000 doses. But as that number is based on assumptions, it willchange as the assumptions change.The following assumptions were used to arrive at the numbers shown in the Volume Forecastspreadsheet: GSK will be ready to launch a malaria vaccine in 2009. The launch will be in SSA. (This does not imply that GSK will not have a vaccine for Asiaand South America; it is only a conservative assumption used for this particular forecast.) The vaccine will initially target infants. Estimated cohort of births in SSA will be 25 million. Uptake will go from 5% to 75% within 15 years. (GSK used measles vaccine uptake inSSA as a benchmark for these assumptions, supposing that malaria was as important adisease to SSA as measles, so the same paradigm could be used.) Two boosters by age five would be required for complete efficacy. Since drugcompliance is a problem in SSA, a pessimistic compliance rate of 20% was assumed.(There was no benchmark for this assumption; there could be an “upside” to the volumeforecast if compliance was underestimated.)9

The estimated “catch-up” for the birth-to-five year cohort will be 125 million, which is anoptimistic figure. Uptake will go from 1% to 50% within 15 years. (There is no benchmark for theseassumptions, but if there is also geographic coverage in Latin America and/or Asia,uptake could be higher and quicker.)These assumptions must then be validated through a sequence of events that involve a multiorganizationalapproach. GSK, in collaboration with other entities such as WHO, MVI, theGlobal Alliance for Vaccines and Immunization (GAVI), and UNICEF, needs to gather moreinformation on an acceptable product profile and the level of commitment of public healthauthorities (PHAs) in developing countries to using such a malaria vaccine. These PHAs alsoneed assurance that they will be able to get financial support to purchase a malaria vaccine.Through regional meetings and other information sharing techniques, clarity on GSK’s initialassumptions will evolve and change over the next several years. Because it takes five years tobuild a factory, whose size depends on projected volume, any manufacturer needs some certaintyas to the number of vaccine doses required annually.VI. Pharmaco-economic Studies of MalariaDr. Anne Mills of the London School of Hygiene and Tropical Medicine (LSHTM) reviewedwhat is known about the C/E of malaria treatment and control from published studies on Africaand summarized the results of the modeling of C/E. The value of a malaria vaccine will bejudged in reference to the C/E of other malaria control tools and other intervention areas(whether malaria or not).The elements of a cost-effectiveness analysis are:The costs of the intervention itself.The health effects of the intervention.The savings in resources or economic benefits. (This element, which should be an importantcomponent of the analysis, often is not included.) Resource savings are derived from theeconomic burden (also called the cost) of malaria, which include such items as: Expenditures by households and governments. Reduced ability of adults to work and/or to care for children. Impact on child development and schooling. Impact on land use. Reduction in incentives to invest in physical and human capital.Knowing the resource savings can help make the case for malaria control over other types ofintervention.10

What is known about cost-effectiveness from the literature?Costs of treatment: Based on studies in six countries, the monthly expenditure by households on malaria-relatedtreatment amounts to up to US$4.00 per person per month. However, the studies are biasedby the fact that the bulk of the data comes from urban areas. Burden on peripheral health facilities: 20% to 40% of outpatient visits in sub-Saharan Africa are for ‘fever’ (most of it probablyfrom malaria); Suspected malaria among inpatients ranges from 0.5% to 50% of admissions, dependingupon the area of sub-Saharan Africa. Cost burden on facilities: Outpatient treatment for suspected malaria cost US$1 in Malawian facilities; Treating severe pediatric malaria in two hospitals on the Kenyan coast cost US$64 and$34 respectively per admission; Pediatric malaria admissions at those hospitals consumed 15% and 9% respectively of theannual recurrent costs of inpatient care.Impact on production: A number of studies estimate days of work lost and the cost of caring for persons sick withmalaria. There is some evidence of impact on child development but mainly in terms of neurologicalsequelae. These studies do not place a monetary value on the cost of damage to a child’sdevelopment. The microeconomic impact (at the household level) on production is probably limited inareas of high transmission, because the main burden of malaria is on children under fiveyears, not on adults. A recent study by Gallop and Sachs suggests a large macroeconomic impact (i.e., to theeconomy as a whole) on production. While this is plausible, only two studies have beenconducted, and more investigation is needed before the order of magnitude is known.Problems with incorporating resource savings into CEA: The evidence collected is on the burden, not the benefits (such as reducing treatment costs),of the intervention. Very few CEA studies estimate resource savings, and where they do (e.g., India), theresource savings are small compared to the intervention costs. Macroeconomic benefits are expressed differently than microeconomic benefits and are thusdifficult to include in any CEA, which is a tool of microeconomics.What is known about the C/E of various malaria control tools:Based on a 1999 literature review, most intervention studies related to insecticide-treated bednets (ITNs). CEA results for interventions show a large range of estimates. The authorsconcluded that it was very difficult to draw C/E conclusions from reviewing existing data,because the studies have different variants and different outcome measures and were done indifferent places. (Even when studies refer to “Africa,” they usually extrapolate data from eitherKenya or The Gambia.)11

Modeling approach used by LSHTM to examine the C/E of existing malaria control tools insub-Saharan Africa, and what was learned: Interventions, where sufficient data existed, were evaluated: malaria prevention in childhood(e.g., ITNs and residual house spraying), malaria prevention in pregnancy (e.g., chloroquinechemoprophylaxis), and some alternative interventions for improving the treatment ofuncomplicated malaria (e.g., improved compliance and improved availability of second- andthird-line drugs). Each intervention evaluated high and low transmission areas, and three different economicstrata were examined. Modeling software that runs Monte Carlo simulations was used. This software gives the C/Eoutput as a probability distribution rather than as a single point estimate. All interventions analyzed in a very-low-income area were very cost-effective (based on costper DALY averted). While C/E data indicates if an intervention will be good value for money spent, further dataand analysis are required to provide information on the actual budgetary costs of theintervention.Conclusion: Data on the C/E of the various existing interventions are relatively weak. Current malaria control interventions in low-income countries are cost-effective. There are major operational difficulties, especially with ITNs, spraying, and attempts toincrease coverage. A potentially misleading feature of C/E is that it is an average cost perunit of effect; it tells nothing about the total population being effected. Preventive measures aimed at the total population (such as spraying or bednets) are costly, infinancial terms, when compared to interventions that target only the segments at greatest risk. Evidence on resource savings is very weak.VII. Demand Forecasting for Developing Country Markets: Lessons LearnedMelinda Moree of MVI addressed some of the issues and problems involved in forecastingdemand for vaccines that are used in developing countries.UNICEF is the main vaccine purchaser for the public sector in developing countries. In thepast year, UNICEF has begun forecasting demand three years ahead, which allowsmanufacturers more time to plan their production to meet the demand.Production planning and overall capacity are huge issues for vaccine manufacturers. Limitedresources restrict manufacturers’ ability to meet the challenges they face. These includescaling up so as to have sufficient supply to meet demands, delivering products on time,quality control, good manufacturing practices (including shelf-life considerations andexpiration dates), logistics, and transportation.A better system is needed for forecasting demand. The public sector and industry cancollaborate to develop an improved model to look at the process of demand forecasting andensure that, within a country, everyone is working with a common set of numbers. GAVI, theGlobal Alliance for Vaccines and Immunization, has taken the lead in developing such a12

process. Advance forecasting is also “tricky”. If the forecast is too optimistic, who bears therisk? How many developing-world vaccine manufacturers can afford such risks?For all tasks related to forecasting, production, and distribution, capacity at the country levelmust be strengthened.It will be challenging to predict malaria vaccine demand in a reliable manner until theproduct profile is better defined. It will, however, be possible to build on other forecastingmethodologies using hypothetical product profiles to better understand the variablesimportant to widespread usage of the vaccine.VIII. Needs for and Uses of Market and Pharmaco-Economic Data: Participants’PerspectivesGeneral consensus existed among the meeting participants about the need for additional, reliablemarket and economic data to inform and guide the malaria vaccine community in efforts todevelop and ensure delivery of an effective malaria vaccine. Participants representing theperspectives of various sectors, identified a range of conditions, market data, and pharmacoeconomicinformation needed. The identified needs are provided under sector headings below.Public sector vaccine development: The overall investment environment for vaccine development needs to be improved; we wantpeople to decide that developing a malaria vaccine is a good investment. Market and economic data can provide a basis for valuing the partnerships between thepublic and private sectors. It must be acknowledged that it will take several players to develop an effective malariavaccine. Defining an acceptable product profile and presentation for a malaria vaccine is crucial. The usual time lag between vaccine launch and its use in developing countries must beshortened. Good estimates of the malaria disease burden and favorable financial arrangements areneeded to drive policy in an informed way.Pharmaceutical industry: There is an immediate need for improved cost data on malaria in children, as well as in adultpopulations. Preliminary in-house modeling results suggest that a vaccine will be cost-effective. Although there is no scientific evidence yet, the feeling is that a 30% efficacious vaccine willnot be enough. For the vaccine to be taken up, decision-makers need to understand vaccine “value” (broadlydefined). These decision-makers have to advocate spending scarce resources and supportexisting (or new) financial vaccine purchasing mechanisms. Phase 3 clinical trials will provide an opportunity to further assess efficacy expectations andsensitive economic parameters.13

Exploring the equity implications of vaccine use. Equity is usually defined as “equal accessfor equal need,” but what are the policy-makers and local health care providers’ approachesto equity?Looking at the consequences of distribution on vaccine availability and assessing theconsequences of vaccine availability on distribution. (Distribution should be an importantfactor affecting demand.)Developing and refining tools that will allow researchers to both measure and value all thepotential benefits of malaria vaccine use—a major challenge.Demographer: Determine the unmet need for a malaria vaccine by regional, sub-regional, and countrylevels. Begin by establishing a baseline using available survey and/or census data on fertility,mortality, and migration. (Epidemiological and demographic data are closely inter-related.) Collect data on demographics, cost, and other indicators to construct regional, sub-regionaland country profiles. Project the immediate, short-term, and long-term need for malaria vaccine. Forecast the short-term and long-term need for malaria vaccine for different segments of thepopulations at risk (e.g., infants, pregnant women, the military, travelers). Anticipateddemand will determine production capacity. Overproduction could lead to long-term storageand eventual wastage. Determine the time for development, marketing, and distribution in the marketplace.Meeting Outcomes, Recommendations, and Potential PartnersA number of outcomes and recommendations emerged from the Malaria Vaccine MarketConsultation, including suggestions that participants considered essential to ensure the future ofmalaria vaccine development and introduction to the developing world. Participants alsoidentified potential partners and supporters of the research effort. All are listed below.I. OutcomesParticipants agreed that this meeting laid the groundwork for future discussions andcollaboration among private and public sector groups interested in funding or conductingstudies that are needed to: Provide better information for policy/decision makers. Improve the investment environment. Systematically plan for the introduction of malaria vaccine.Participants agreed that MVI staff would prepare, for future review and comment byparticipants, the framework of a research agenda based on knowledge gaps identified andrecommended for future study by the meeting participants. (The timeline for the researchagenda is based on an assumption that a malaria vaccine meeting and agreed upon productprofile will be ready for endemic country introduction within ten years.)16

Participants acknowledged the need to use common methodologies and share study protocolsas well as preliminary and final results of studies undertaken.Participants agreed that future research efforts will be so organized as to ensure a coherentand coordinated approach to supporting the achievement of a shared goal—the developmentof a safe, acceptable, and efficacious malaria vaccine suitable for introduction in Africa.II. RecommendationsParticipants identified studies, related information needs, and activities. These were then looselyorganized according to the time frame in which they would be undertaken: Stage #1 begins now (ten years from licensure) and reflects immediate needs to be addressedas soon as funding is available. Stage #2 is the period five to seven years from licensure. Stage #3 is the period immediately prior to and during vaccine launch.Further prioritization will be reflected in the forthcoming research agenda framework. To avoidduplication, a search for existing studies should be undertaken as a near-term priority activity.Stage # 1: Ten years from licensure: An immediate research agendaNote: Activities that overlap should be implemented simultaneously.Vaccine profile Define the questions essential to ensuring development and introduction of an acceptablevaccine. Reach consensus on the definition of a minimally acceptable malaria vaccine profile to beused by all persons/groups within the malaria vaccine community. What is the profile of avaccine that is acceptable to stakeholders and will impact disease burden? How efficaciouswill it be? Will it prevent or mitigate disease? How many boosters will it require, and at whatintervals? Learn more about how vaccine characteristics would influence national decisions tointroduce a vaccine. (This information also should be part of any vaccine profile.) Begin epidemiological studies that will help concerned stakeholders understand theimplications of a range of decisions and policies related to the profile and presentation of avaccine. Epidemiological data are also necessary for defining the product profile on whichmarket studies will be based. Develop a tool that can be used to halt development of vaccine candidates that will not reachthe agreed-upon minimally acceptable profile. Fully consider the implications of vaccine development driven by the public sector to addressa disease that primarily affects the developing world. What is risked by implementing apartially effective vaccine? What is risked by not implementing a partially effective vaccine?What will drive vaccine improvements after introduction?17

Create economic models supporting the case for investing in malaria vaccine development. Amodel is needed that can help determine what proportion of malaria is preventable throughuse of a malaria vaccine.Begin logistics forecasting to anticipate the costs of vaccine transport, storage, and delivery.Develop plans for funding marketing studies and vaccine introduction. Reach out to allgroups that will put supportive financial systems in place.Other Determine whether and how to quantify the economic benefits of saving infants andchildren’s lives and reducing morbidity in countries with high birth rates. Create a planning flow chart of the various studies that need to be done at the differentstages. Assess unmet need and the size of the population at risk, by country, region or subregion. Define notional malaria vaccines—i.e., products with a set of defined characteristics thatmight exist in the future (based on those in development or those we would like to haveavailable) -- that can be used for these various analyses. Look at the operational aspects of a proposed vaccine program using an initial public offeringmodel, i.e., emphasizing input, process, and outcome. C/E and cost-based analysis studieslook at outcomes, but for a vaccine program, it is essential to develop a set of key indicatorsof success at the very beginning. These indicators can be determined through a mini censusin combination with focus group discussions with stakeholders. This will establish a baselineand enable planners to assess what is already known and also determine what new data needto be collected.Stage # 2: Five to seven years from licensure Hold three regional meetings (Africa, Asia and Latin America) to gain consensus from local,public, and private sector policy and decision makers on how they perceive/believe anymalaria vaccine will be used—and by which cohort(s). This will give potential manufacturersinformation essential to their planning and decision-making around production capacity: sizeof plant, number of doses, and whether to plan for mass or limited production schedules. Conduct infrastructure studies to look at how distribution can be integrated into existing EPIand how to improve distribution, especially in rural areas. Investigate delivery systems in the informal health sector, including injectionists,pharmacists, traditional healers, and employers. Determine in advance what universal benefits to measure when introducing the vaccine. Using results from Stage # 1 studies, outline a C/E model. Agree on which health outcomesare most desirable. Look at implications of various introduction strategies such as targetedcoverage vs. mass immunization campaigns, and answer related questions: What are additional costs of targeting adolescents and/or other cohorts? What are the added costs of using a combination vaccine? What is the cost of using vaccine as a complement to—or substitute for—existing malariacontrol strategies? Will a new infrastructure need to be created? (At this stage it is more important to model theeffects than the costs). Obtain funding to build local capacity to conduct C/E studies.19

Begin collecting cost data while conducting Phase 2 and Phase 3 clinical trials. Use a flexiblemodel that can capture changing situations, such as the introduction of competing productsand new delivery systems. Research what donors and endemic-country governments arewilling to pay.Initiate pre-marketing studies in conjunction with Phase 3 clinical trials. There should besufficient data to refine the natural history model and predict the potential vaccine’s impact.Determine and reach consensus on which methodology will be best for testing proposedinterventions.Once Phase 3 clinical trial results are known, complete the C/E model, finalize demandforecasts at the regional and country levels, and develop an action plan. Vaccine ordersshould be placed about two years before the product launch.Begin developing an introduction strategy.Stage # 3: Immediately prior to and during product launch Identify several geographic areas where it will be possible to monitor and document theeffects of the vaccine. Based on what is learned, global and country-specific policy changescan be made if necessary. Identify sites for long-term, post-licensure evaluation. Measure outcomes against pre-determined impact indicators, not simply by number of dosesdelivered. Define feedback mechanisms. Anticipate the impact of introducing a minimally effective vaccine on future vaccinedevelopment. How good must the next generation of vaccines be in order to be considered? Acknowledging that different countries may want to introduce the vaccine in different ways,revisit the question of alternative delivery mechanisms. It will be necessary to consider thechanging capacities and budgets at the country level and how these will affect countries’abilities to implement any malaria vaccine program. The entire range of decision makers’perspectives, both at the national and sub-national levels, should be taken into account. To ensure proper access and delivery, implement the training plan that was developed duringStage #2. It might be necessary to get governments and individuals to change their thinking about whatconstitutes a “vaccine.” At present many people regard vaccines as 100% effective; anythingless is considered a failure, and thus of little or no interest. Conduct small market studies todetermine if it is better to promote this new product as a “malaria inhibitor” or “malariareducer” -- in order to focus purchasers’ minds on the actual benefits. Can such a small stepas a name change people’s expectations as to what this new product can achieve, or will itconfuse them?III. Potential Partners/FundersParticipants identified the following organizations and programs as being essential to moving anintegrated malaria economic analysis research agenda forward. It is assumed that these lists willbroaden and provide a common basis for research, funding, and partnership formation during thenext two years.20

The Fogarty International Center, National Institute of Health (NIH).The World Bank (support for modeling research).Willing industry partners.Foundations established by pharmaceutical companies, such as The Wellcome Trust, whichhas funded research on combination therapy for malaria.UK Department for International Development (DFID) supports malaria research, but doesso mainly through grantees in the UK.The United Nations Development Programme/World Bank/WHO Special Programme forResearch and Training in Tropical Diseases (TDR).Roll Back Malaria.The U.S. Centers for Disease Control and Prevention (CDC).USAID, for research directed to country level efforts.The Global Alliance for Vaccines and Immunizations (GAVI).The Johns Hopkins University.London School of Hygiene and Tropical Medicine.Malaria Vaccine Initiative, PATH.Institutions and individuals from developing countries.The Malaria Vaccine Initiative (MVI) is a global program established through an initial grant from the Bill &Melinda Gates Foundation to Program for Appropriate Technology in Health (PATH). MVI’s mission is toaccelerate the development of promising malaria vaccines and ensure their availability and accessibilityfor the developing world. MVI’s vision is a world where vaccines protect children from death and severedisease caused by malaria. For information, visit www.MalariaVaccine.org.PATH is an international organization dedicated to developing, implementing, and evaluating innovativesolutions to public health problems. PATH’s mission is to improve health, especially the health of womenand children. Visit PATH’s Web site at www.path.org.21

Appendix 1Malaria Vaccine InitiativeMalaria Vaccine Market ConsultationDoubleTree Hotel, Rockville, MarylandDecember 10-11, 2001Meeting AgendaDay 1 ~ Monday December 10, 20018:30am - 9:00amCoffee and Greeting9:00am - 9:30am Introduction and Opening Remarks R. RabinovichIntroductions and logisticsR. SteinfieldMeeting Goals and IntentM. Moree9:30am - 10:30amOverview of Presentations Overall Market Information/Market Analysis 101 T. Darcis/W. VandersmissenC. Marcos Pharmacoeconomic Studies for Introduction J. Fox-Rushby Case Studies: HIV Y. Madrid10:30am - 11:00amBREAK11:00am - 12:00pm Presentations: Needs & Uses for Economic Data M. Moree (moderator)Objective: Address key market data and pharmacoeconomic information, and lay outorganizational needs. Malaria Vaccine Initiative (MVI) M. Moree Global Policy & Financing A. Batson Big Pharma GSK team Biotech D. Broderick Country/Introduction Issues A. Mills/J.Fox-Rushby LSHTM Gates Program V. Wiseman Donor C. Diggs12:00am - 1:00pmLUNCH

Appendix 11:00pm - 2:15pm Discussion: Needs & Uses for Economic Data R. Widdus (moderator)Objective: Identify the needs for economic data for malaria vaccines and discuss theopportunities and limitations of market and pharmacoeconomic data.2:15pm - 5:00pm Discussion: Project Specifics & Methodology J. Fox-Rushby (moderator)Objective: Review existing market and pharmacoeconomic data on malaria vaccines and areview of relevant methodology.2:15pm - 3:15pm MVI Market Assessment L. Barnard Industry analysis of malaria vaccine market demand and healtheconomy/pharmacoeconomicsGSK Team Malaria Specific Pharmacoeconomic Studies A. Mills3:15pm - 3:45pmBREAK3:45pm - 5:00pm Demand Forecasting for developing country markets--lessons learned M. Moree Demand Creation Demographic Perspectives: Factoring time of development into marketassessmentsP. Yu/C. Indocochea6:30pmDINNERDay 2 ~ Tuesday December 11, 20018:30am - 9:00am9:00am -10:00am10:00am -10:30am10:30am - 11:30amDiscussion: Related Topics of InterestDiscussion: Data NeedsBREAKDiscussion: Filling the Information Gap11:30am - 12:00pm Conclusions

Appendix 2Malaria Vaccine InitiativeMalaria Vaccine Market ConsultationDoubleTree Hotel, Rockville, MarylandDecember 10-11, 2001List of ParticipantsLisa BarnardConsultant4720 Chevy Chase Drive, #500Chevy Chase, MD 20815Phone: +1 240 401-3312Email: lbarnar@attglobal.netAmie BatsonSenior Health SpecialistHealth, Nutrition & Population UnitThe World Bank1818 H St. N.W.Washington, D.C. 20433Phone: +1 202 458 8300Fax: +1 202 522-3489Email: abatson@worldbank.orgDaniel BroderickDirectorBusiness DevelopmentApovia Inc.11125 Flintkote AvenueSan Diego, CA 92121Phone: +1 858 558-5888 ext. 213Fax: +1 858 558-3870Email: d.broderick@apovia.comDr. Thierry DarcisDirector, New Product DevelopmentGlaxoSmithKline89 rue de l'Institut1330 Rixensart, BelgiumPhone: +32 2 656 93 19Fax: +32 2 656 81 28Email: thierry.darcis@gskbio.comCarter Diggs, MD, Ph.DSenior Technical AdvisorMalaria Vaccine Development ProgramU.S Agency for International Development1300 Pennsylvania Avenue, N.W.Washington, D.C. 20523-3700Phone: +1 202 712-5728Fax: +1 202 216-3702Email: cdiggs@usaid.govAmy Ekola DyeAssociateBurness Communications7910 Woodmont Avenue, Suite 1340Bethesda, MD 20814-3015Phone: +1 301 652-1558Fax: +1 301 654-1589Email: aekola@burnesscommunications.comJulia Fox-Rushby, Ph.DDepartment of Public Health and PolicyLondon School of Hygiene & Tropical MedicineKeppel StreetLondon WCIE THT, United KingdomPhone: +44 207 926 2267Fax: +44 207 636 5391Email: julia.fox-rushby@lshtm.ac.ukCarol HooksSenior Communications OfficerMalaria Vaccine Initiative, PATH6290 Montrose Road, Suite 1000ARockville, MD 20852Phone: +1 301 770-5377Fax: +1 301 770-5322Email: chooks@malariavaccine.org

Appendix 2Carlos Manuel IndacocheaSenior Researcher, Writer, and EditorAARPPhone: +1 202 434 2532Fax: +1 703 204 3401Email: cindacochea@aarp.orgStephanie James, Ph.D.Deputy DirectorThe Ellison Medical Foundation4710 Bethesda Ave., Suite 204Bethesda, MD 20814-5226Phone: +1 301 657-1830Fax: +1 301 657-1828Email: sjames@emf.ipmail.att.netYvette MadridConsultantInternational AIDS Vaccine Initiative30 rue de la Gabelle1227 Carouge, SwitzerlandPhone: +41 22 301 80 30Fax: +41 22 301 80 33Email: ymadrid@iavi.orgCamelia MarcosManagerNew Product DevelopmentGlaxoSmithKline BiologicalsRue de l’Institut 89B-1330 Rixensart, BelgiumPhone: +32 02 656 92 44Fax: +32 02 656 81 28Email: camelia.marcos@gskbio.comAnne MillsHeadHealth Economics and FinancingProgrammeLondon School of Hygiene and TropicalMedicineKeppel StreetLondon WC1E 7HT, United KingdomPhone: +44 207 927 2354Fax: +44 207 637 5391Email: anne.mills@lshtm.ac.ukJessica MilmanProgram OfficerMalaria Vaccine Initiative, PATH6290 Montrose Road, Suite 1000ARockville, MD 20852Phone: +1 301 770-5377Fax: +1 301 770-5322Email: jmilman@malariavaccine.orgMelinda MoreeBusiness Development OfficerMalaria Vaccine Initiative, PATH1455 NW Leary WaySeattle, WA 98107Phone: +1 206 285-3500Fax: +1 206 285-6619Email: mmoree@path.orgRegina RabinovichDirectorMalaria Vaccine Initiative, PATH6290 Montrose Road, Suite 1000ARockville, MD 20852Phone: +1 301 770-5377Fax: +1 301 770-5322Email: rrabinovich@malariavaccine.orgRebecca SteinfeldProgram AssociateMalaria Vaccine Initiative, PATH1455 NW Leary WaySeattle, WA 98107Phone: +1 206 -285-3500Fax: +1 206 285-6619Email: rsteinf@path.orgEveline TierneyProgram OfficerMalaria Vaccine Initiative, PATH6290 Montrose Road, Suite 1000ARockville, MD 20852Phone: +1 301 770-5377Fax: +1 301 770-5322Email: etierney@malariavaccine.org

Appendix 2Jodi UddProgram AssistantMalaria Vaccine Initiative, PATH1455 NW Leary WaySeattle, WA 98107Seattle, WA 98109Phone: +1 206 285-3500Fax: +1 206 285-6619Email: judd@path.orgMargot Lurie ZimmermanConsultant7902 Rocton AvenueChevy Chase, MD 20815Phone: +1 301 656-5764Fax: +1 301 656-5764Email: mandpzimm@starpower.netWalter VandersmissenDirectorGovernment AffairsGlaxoSmithKlineRue de l’Institut 89B-1330 Rixensart, BelgiumPhone: +32 02 656 83 70Fax: +32 02 656 81 45Email: walter.vandersmissen@gskbio.comVirginia WisemanHealth EconomistGates Malaria ProgramLondon School of Hygiene & TropicalMedicine50 Bedford SquareLondon WC1B3DP, United KingdomPhone: +44 (0)20 7299 4716Fax: +44 (0)20 7299 4720Email: virginia.wiseman@lshtm.ac.ukPing Yu, Ph.D.Health Research DirectorCenters for Public Health Research andEvaluationBattelle2101 Wilson Boulevard, Suite 800Arlington, VA 22201-3008Phone: +1 703 875-2981Fax: +1 703 527-5640Email: yup@battelle.org

Appendix 3Acronym ListAIDA – Awareness, interest, demand, and adoptionCBA – Cost/benefit analysisCDC- Centers for Disease Control and Prevention (US)C/E – Cost-effectivenessCEA – Cost-effectiveness analysisCUA – Cost utility analysisDALY – Disability-adjusted life yearsDFID – Department for International Development (UK)EPI – Expanded Programme on ImmunizationFGD – Focus group discussionGAVI – Global Alliance for Vaccines and ImmunizationGSK – GlaxoSmithKline BiologicalsIAVI – International AIDS Vaccine InitiativeITN – Insecticide-treated bed netLSHTM – London School of Hygiene and Tropical MedicineMVI – Malaria Vaccine InitiativeNGO – Non-governmental organizationNIH – National Institutes of Health (US)NPV – Net present valuePATH – Program for Appropriate Technology in HealthPHAs – Public health authoritiesQALY – Quality-adjusted life yearsSSA – Sub-Saharan AfricaTDR – Special Programme for Research and Training in Tropical DiseasesUK – United KingdomUNAIDS – Joint United Nations Programme on HIV/AIDSUNICEF – United Nations Children’s FundUS – United StatesUSAID – United States Agency for International DevelopmentWHO – World Health OrganizationWTP – Willingness to pay