Attribute Description
1.  Context
1.1   Objectives and scope Each investment case should begin with a concise introduction that provides critical context about the motivation and objective for the investment case.  It should also clearly identify the scope and time horizon of the analysis and demonstrate the need for potential global coordination of the investment for the disease(s) considered (i.e., demonstrate the interdependencies that nations face with respect to disease management that necessitates the development of an investment case).  
1.2   Description of the disease and its global health significance Each investment case should include a very brief description of the disease and existing and potential interventions for its management, and summarize the current state of any efforts to globally coordinate disease management.  The discussion of global health significance should describe the extent to which heterogeneity exists with respect to current disease-related mortality and morbidity and disease management efforts, address issues related to the ability of the disease to spread regionally and globally, and identify important issues further developed in other sections of the investment case.  If the investment case includes eradication as an option then it should present evidence of some demand for eradication and willingness to cooperate at the global level.
1.3   Role in the portfolio of coordinated global health priorities The investment case should briefly describe the status of the disease(s) considered in the investment case in the context of the overall portfolio of coordinated global health priorities and discuss the degree of alignment of the investment case with any existing global vaccine strategic plans (e.g., Global Immunization Vision and Strategy (GIVS), 2006-2015; Global Vaccine Action Plan (GVAP)) [11,12]. This part should provide context about the collection of all similar investment cases and include a high-level discussion of current global health priorities (i.e., those with greatest global political and/or financial commitments or other internal and/or external investments of any type) in the context of the overall portfolio.
1.4   Process Any investment case will reflect the information available at the time of its preparation and the process used to prepare it.  Consequently, this part of the investment case should summarize the process used to prepare it.  Further, given the anticipated desire and/or expected need to maintain an investment case as a “living document” that evolves over time as conditions change, the discussion in this part should provide details about any important reasons for major changes (e.g., achievements of milestones, recognition of barriers and/or unanticipated events that lead to modifications of plans or expectations, etc.)  The discussion should also summarize the lessons learned and iterations in the investment case over time and provide the reader with context related to the evolution of the investment case.
2.  Current path
2.1   Mechanisms of disease transmission The investment case should provide a description of the current state of knowledge about the nature of the disease and its transmission (including any host reservoirs).  This should include discussion of the biological feasibility of eradication of the disease.
2.2   Current treatments for the disease The investment case should provide details about the health effects caused by the disease and current standards of care with respect to treatment.  This part should address any variability that currently exists with respect to treatment due to differences in the structure and utilization of health systems.
2.3   Current global strategies for surveillance The investment case should provide a synthesis of the methods used for infection and/or disease surveillance and describe the current state and quality of surveillance evidence and context that might impact the interpretation of historical data provided by the surveillance system (e.g., historical development of methods, standards, and regional and/or global networks).  For diseases considered eradicable biologically (discussed in 2.1), the investment case should discuss the technical feasibility of deploying surveillance activities sufficient to support globally-coordinated disease management efforts like those required to eradicate the disease and to confirm the absence of the pathogen with high confidence.  This part should consider the need for sustainability of surveillance systems for the disease over time.
2.4   Existing interventions to prevent or stop transmission The investment case should provide a description of the current state of knowledge of the interventions that exist to protect humans from the disease and/or prevent its transmission, which should focus on synthesizing evidence of the effectiveness and practicality of the existing interventions.  For diseases considered eradicable biologically (discussed in 2.1), the investment case should discuss the technical and programmatic feasibility of deploying the existing preventative interventions globally.
2.5   Current expected global level of control (i.e., the status quo) Recognizing that countries and regions may progress through various phases of exposure to the disease (e.g., emergence, endemic, epidemic) and control (i.e., none to eradication) [8,9] the investment case should summarize the current state of the world with respect to the geographic distribution of the disease and its control with characterization of the heterogeneity of disease burdens.  The discussion should provide context about outbreaks and the extent of implementation of the existing interventions for prevention and in reaction to outbreaks (discussed in 2.4).  This part should also synthesize the available data and the results of appropriate mathematical models used to define the status quo path, which reflects the past, current, and expected planned investments of countries with respect to control of the disease and represents the expected global baseline for comparison.  Stakeholders may differ with respect to their perspectives on the current path (discussed in 2.5), and in this case the investment case should highlight underlying reasons for different perspectives and identify the need to recognize either more than one potential current path or different perspectives as alternative paths (discussed in section 3).  Any regional and/or global minimum commitments agreed to by all countries will determine the minimal activities with respect to implementation of interventions, but individual countries can always exceed the minimum and the investment case should anticipate heterogeneity [27]. In the context of characterizing the current path, the investment case should synthesize the available historical data, model results, and other information about the disease burden up to the current time with consideration of any uncertainty related to the lack of perfect surveillance (discussed in 2.3).  In addition, the investment case will need to forecast the expected future investments based on extrapolation from the past, current practices, and/or existing national, regional, and/or global commitments.  Given the need to project into the future, the investment case may need to include more than one potential expected current or status quo path to account for uncertainty (e.g., unknown national and regional commitments to various interventions and/or inadequate evidence of secure financial support for existing commitments).  The investment case must make any assumptions about projections transparent and demonstrate the impact of different potential projections with respect to the characterizations of the burden of disease, which may warrant elaboration in the context of uncertainty and/or sensitivity analyses (discussed in 2.9).  The discussion should also highlight any major issues that currently interfere with greater success of the current path (e.g., refusal of an intervention by specific groups and/or in some geographic areas).
2.6   Characterization of current financial costs The investment case should synthesize the evidence about the financial costs of the expected current or status quo path(s).  This should include projected, expected and realistic (i.e., not optimistic) costs of all of the interventions out over time, using a consistent currency year with all costs discounted back to the current time using a rate of 3% [1,32]. The investment case should present appropriate break downs of the expected costs for regions and/or individual countries to the extent required to support the global analysis.  The investment case should clearly state any assumptions related to projections of prices and utilization of the interventions consistent with the assumptions used to define the status quo path(s) (discussed in 2.5) and it should take care to factor in the impact of any time delays and unplanned events (i.e., include costs associated with the expectation of the need to implement contingency plans, discussed in 4.3).  The investment case should reflect a societal perspective and characterize the direct costs of the interventions with quantification of indirect financial costs to the extent possible.  It should also discuss different perspectives (e.g., health system, intervention manufacturer, individual) to highlight and discuss financial incentives faced by various stakeholders.  The cost analysis should include the savings of health care treatment costs avoided due to the interventions, which implies that if the interventions themselves save money on net (i.e., if the interventions cost less than the amount of health care costs that society would spend to treat cases in the absence of the interventions), then the characterization of costs would imply net savings or a negative financial cost for the interventions.  To the extent that the current path includes add-on or cost-sharing activities (e.g., giving vitamin A as part of polio or measles immunization campaigns, shared surveillance platforms), the analysis should separately quantify the costs of those activities and/or the impact of cost-sharing.
2.7   Characterization of current health benefits The investment case should synthesize the evidence about the health benefits of the current status quo path(s), building on the information in 2.5.  This part should include discussion and use of different metrics that effectively address the needs of stakeholders to understand and communicate the health benefits of the current path (e.g., cases prevented, deaths prevented, disability-adjusted life years (DALYs) saved), and synthesize the available evidence related to economic valuation of the health benefits recognizing that countries may differ significantly with respect to their values [8,9]. This analysis should discuss assumptions about valuation of the health effects and present results in the context of the variability and uncertainty that exists about the values that countries place on health and it should attempt to capture the true net societal costs of the current path.  To the extent that the current path includes add-on or cost-sharing activities (e.g., vitamin A delivery as part of polio or measles immunization campaigns), the analysis should separately quantify the health benefits of those activities and costs attributed to the interventions (discussed in 2.6).
2.8   Synthesis of the economics of the current investment The investment case should synthesize the overall evidence and provide the results of the economic analysis of the current path(s).  This synthesis should also describe the current financial and political commitments that support investments made by stakeholders in the current path, and discuss the implications for the current path if these change over time. 
2.9   Limitations and uncertainties The part should discuss key uncertainties, limitations in the evidence, and other issues that may potentially impact the assessment of the current or status quo path(s), burden of disease, cost, and valuation estimates.  The discussion should highlight any major issues that currently interfere with greater success of existing control efforts and identify the impacts of different assumptions on any quantitative results provided about the current path in appropriate sensitivity and/or uncertainty analyses. 
3.   Alternative paths
3.1  Alternative global options for control and/or eradication (including post-eradication) Building on the foundation developed about the current situation (discussed in section 2), the investment case should identify the full set of potential options that exist for alternative levels of investment in global management of the disease from a decision point (i.e., a time zero or T0 for the change of path).  Alternatives should explore different disease control targets (e.g. mortality reduction, eradication, and possibly regression or less control), different time lines for achieving those targets, and different timing, with full recognition of the potential for shared or competitive use of scarce resources.  These should include appropriate details about the relevant expectations for individual countries and/or regions at and after T0 for each alternative option (recognizing that nations and/or regions may start in different places given the variability in their current strategies discussed in 2.5).  For any eradication alternative(s) the investment case should include a specific plan for achieving eradication with a proposed timeline, projections about how the world will look after eradication is achieved, and discussion of expected post-eradication activities (e.g., expected needs for continued surveillance, intervention, intervention supply stockpiles, and/or outbreak response capabilities).  The alternatives should also consider any potential add-on activities that may also lead to cost-sharing opportunities.
3.2   Global intervention supply For each potential alternative (identified in 3.1) the investment case should determine whether sufficient supplies of interventions and diagnostic tools exist to support implementation of the alternative and intervention supply security, particularly in the context of ongoing development of potentially more profitable products by intervention manufacturers.  The information presented in this part may lead to iteration and adjustment of the options or reduction in the set of alternatives carried forward in the remainder of section 3.  The analysis should carefully consider the timelines required for any efforts to ramp up production to ensure that the alternative paths reflect real possibilities and to ensure consistency with estimates of resource requirements (discussed in 3.4).  The estimates should also include the possibility of intervention supply disruptions and any reserves or stockpiles that may exist or need development.  If outbreak response efforts for the disease(s) considered in the investment case or for other public health emergencies compete for intervention resources, then the investment case will need to discuss the management of this competition, and/ or if opportunities exist to share resources, then the investment case needs to characterize the potential benefits of sharing.
3.3   Global system implementation capacity The investment case should provide details about whether the existing systems (including surveillance and intervention delivery) exist to support implementation of each alternative.  The information in this part may lead to iteration and adjustment of the options (identified in 3.1) or reduction in the set of alternatives carried forward throughout the remainder of section 3.  The analysis should carefully consider the timelines required for any efforts to build capacity to ensure that the alternative paths reflect real possibilities and to ensure consistency with estimates of resource requirements (discussed in 3.4).  If creating and sustaining health systems capable of supporting delivery of the interventions represents an issue, then the interventions will need to identify strategies for addressing inadequacies (e.g., recruitment and training of dedicated staff, performing supplemental immunization activities) and ensure sufficient resources exist to support these activities (discussed in 4.2).  If insufficient resources exist or cannot reasonably be anticipated to exist, then the alternative does not qualify as realistic and would not carry through to the remainder of section 3.  The investment case should provide a plan for ensuring no net harm to health systems associated with the alternative, and characterize any expected net benefits to health systems associated with implementation of the alternative.  In addition, if outbreak response efforts for this disease or for other public health emergencies compete for capacity, then the investment case will need to discuss the management of this competition.
3.4   Expected financial costs of the alternatives For each of the feasible alternatives, the investment case will need to estimate the associated financial costs and its incremental cost compared to the current or status quo path(s).  The analysis should use the same dollar year, discount rate, and assumptions to ensure fair comparisons with the costs of the current path(s) (discussed in 2.6).  The expected costs should identify opportunities to share costs (i.e., potential synergies) between interventions and/or with other existing or potential efforts, but it should cost these separately such that the cost estimates do not depend on the occurrence of other actions (i.e., the cost estimates should reflect the resources required to pursue each alternative independently or together with clear linkage to and consistency with assumptions about timing).  In addition, the investment case should include estimated global programmatic costs associated with each alternative, if implementation of the alternative requires an additional investment.  For example, for an alternative that pursues eradication, the incremental global programmatic costs may need to include resources required to expand surveillance networks, social mobilization, laboratory and health worker resources, and volunteer capacity and/or to support communications (including social, anthropological, and behavioral) and operations research.
3.5   Expected net benefits of the alternatives The investment case should quantify the expected net health benefits of the alternatives using the same metrics and approaches used for the current path(s) (discussed in 2.7) and present the incremental net benefits for each alternative.  The investment case should also identify potential positive and/or negative indirect impacts, including effects on health systems, for each option and quantify the impacts to the extent possible (with qualitative considerations discussed in section 4).
3.6   Expected political and financial commitments   The investment case should identify the expected required political and financial commitments needed to support the various alternative paths, including critical factors for securing required commitments and global agreements.  The discussion should also address how the alternatives in the investment case relate to other control and/or eradication initiatives in the global portfolio (discussed in part 1.4) and issues of competition and opportunities for synergies.  This part should discuss the implications of potential changes in political, financial, and other resource commitments and investments, including consideration of the impact of delays of other global health initiatives leading to the potential of delayed or limited availability of resources.
3.7   Synthesis of the economics of the alternative investments The investment case should synthesize overall evidence and provide an economic analysis of the expected alternatives compared to the current status quo path(s).  This part should present estimates of incremental cost-effectiveness and net benefits for the alternatives compared to the current path(s) at the global level and, as needed, for individual countries and/or regions.  For each alternative, the investment case should identify key milestones for tracking progress along the expected path.   As needed, the investment case should present different metrics that may prove useful to different stakeholders and/or references for comparison (e.g., costs per capita compared to the health sector budget, costs of other initiatives).
3.8   Limitations and uncertainties The last part of the discussion of the alternatives should describe key uncertainties, limitations in the evidence, and other issues that may potentially impact the assessment of the alternatives and the associated burden of disease or cost estimates.  The discussion should highlight any major considerations (discussed in section 4) and provide the results of any sensitivity and/or uncertainty analyses performed.  This part should demonstrate the impacts of explicit choices regarding valuation of health outcomes and nonmonetary benefits on the economic analyses.
4.   Considerations
4.1   Broad social impacts   The investment case should discuss the differences in broader social impacts, including intergenerational benefits, equity (e.g., reaching marginalized populations), and social value for any investment case that includes alternative paths for which the social impacts differ from each other and/or the current path(s).  If the investment case includes eradication as an alternative path it should consider the change in the nature of the public good and/or any social dilemmas that arise compared to the current path(s).  This part should highlight any metrics of equity that might support discussion of the alternatives based on different criteria than the economics (e.g., percent of children reached through SIAs not otherwise currently reached).  The discussion in this part should focus on significant differences related to the alternative paths compared to the current path(s), but also consider issues related to the societal effects of not meeting milestones for current commitments on the likelihood of support for future efforts, including the impacts of failing to deliver on prior promises recognized as overly optimistic with the passage of time.   The investment case should consider the impacts of the current and alternative paths on social norms and expectations for health.
4.2   Impact on health systems The investment case should provide an assessment of why existing health systems stratified by relevant categories or types currently perform the way they do with respect to management of the infection(s) and disease(s) considered in the investment case.   This analysis should identify the areas with the weakest, most fragile health systems and provide detailed plans for addressing the issues in these areas required to meet the targets associated with the current and alternative paths.  The investment case should also identify a proposed process for active evaluation of any positive or negative impacts on health systems.  The analysis of health systems should explicitly consider the sustainability of resources required to provide health services and infrastructure capacity, including overall cold chain demands and requirements and access to all areas (e.g., security, roads or other transport).  The investment case should consider the potential impact of positively and/or negatively distorting the current incentives of stakeholders by introducing new resources (e.g., providing resources to build health worker capacity in weak health systems characterized by overloaded and stretched staff may inadvertently create dependency on external funds).
4.3   Management and governance The investment case should describe the management and organizational structures required for the current and alternative paths and describe the existing and expected roles and commitments of stakeholders for the current path and any differences in requirements for the alternative paths.  The organizational structure should address all levels and their connections, and provide clarity about the management and governance of any activities coordinated globally and/or regionally.  The investment case should also describe the expected tools and process for monitoring and evaluating progress toward milestones (discussed in 3.7) and responsibilities related to managing coordination, cooperation, and shared resources.  In the context of an alternative path that includes eradication, this part should describe the specific organizational roles and responsibilities related to outbreak response, stockpile, surveillance, and other global programmatic activities.  This part should address any issues of institutional capacity to provide programmatic support to engage stakeholders at all levels.  For stakeholders that lack sufficient resources, the investment case should address the community level and/or national costs, perceptions, and/or incentives that may motivate and/or discourage individuals, governments, and/or organizations from doing the work required to achieve the milestones. 
4.4   Stakeholder engagement Achievement of milestones associated with the current and alternative paths will require the engagement of a broad group of stakeholders, including governments at all levels, donors, intervention manufacturers, civil society and non-governmental organizations (including professional societies, community groups, etc.), and individuals (who will need to accept and demand the interventions, perhaps on behalf of others in the case of parents making choices for their children).  The investment case should provide details about plans for communication with stakeholders to engage them in the deliberative process to chart the preferred course and ensure alignment of their perceptions about the preferred course and incentives for them to support its implementation.  To the extent that various stakeholders hold competing objectives, the investment case should make these clear and discuss potential opportunities for compromise and negotiation in addition to exploring the implications of the overall mixed messages that may arise.  This part should include discussion of the expected roles and responsibilities of various stakeholders, and discuss the need for and the expected process for performing research related to understanding and managing perceptions related to the current and alternative paths.  This should include an assessment of communication risks and discussion of expected communications efforts to engage stakeholders to address the risks identified (discussed in 4.5).   The investment case should discuss the need for stakeholders to make and maintain commitments in the context of success, when the absence of cases of illness or disease may lead to misperceptions that individuals/countries/ regions no longer need the intervention, and/or in the context of failures, when the resurgence of cases of illness or disease may undermine confidence and demonstrate the fragility of prior gains. 
4.5   Risks and contingency plans The investment case should clearly identify key risks and describe the detailed contingency plans that exist for their management.  The investment case should anticipate challenges and constraints of all types (ethical, geopolitical, social, economic, epidemiologic, technical and institutional) for the alternatives that differ from the current path(s) and demonstrate plans and strategies to address these, including the allocation of resources to implement the contingency plans.  In particular, this part should address issues related to maintaining progress toward the milestones in the context of financial crises, political strife or instability, and other emergencies.  Given the reality that settings and situations differ (e.g., interventions and strategies that prove effective in some places may not perform as well in others), the investment case should consider the impact of uncertainties related to extrapolation to new conditions and provide context that will help stakeholders manage their expectations.  The investment case should encourage the thorough investigation of the underlying causes of outbreaks, because outbreaks may represent failures of strategy, commitment, and/or implementation and global management efforts should apply the lessons learned from outbreaks to other areas with similar risks.
4.6   Research and development   The investment case should discuss the role of research with respect to resolving important sources of uncertainty and achieving the milestones for the current and alternative paths.  It should also identify knowledge gaps and research needs that will support the development of a process for supporting ongoing research, particularly operational and communications research, which may prove pivotal to success in some communities.  The investment case should discuss the development of new tools that may lead to more cost-effective interventions.  For significant basic research questions (e.g., pathogenesis, the mechanistic basis for the effectiveness of an intervention), the investment case should identify key questions and encourage the investigation of promising lines of research.
4.7   Timing in the context of the portfolio of globally-coordinated disease management efforts   The global management of infectious diseases represents an ongoing process.  Major initiatives may in some cases benefit from synergies associated with shared use of infrastructure and/or other resources and in other cases they may compete for scarce resources (e.g., funding, political attention, health system and human resources, public and media attention).  The investment case should provide context about the overall portfolio of global disease management efforts (discussed in part 1.3) and explore how the alternatives may benefit from synergies and/or may encounter additional challenges with respect to the timing of their implementation.   This part should explore alternative timing options beyond those discussed in section 3 and address any important qualitative considerations (e.g., issues related to political will).
4.8   Financing The investment case should consider the opportunities that may exist for financing globally-coordinated efforts and how the investment case fits into the context of the overall portfolio of global disease management efforts (discussed in 1.3) and/or global health efforts more broadly to the extent possible.  In the context of discussing potential financing, the investment case should focus on anticipated opportunities and challenges that may exist given other global commitments (e.g., building on the infrastructure of an existing eradication initiative, competing for a fixed pool of funds) and the potential impact on financing.
4.9   Oversight and iteration The investment case should discuss the planned process for oversight of global and regional coordination of efforts and consider the potential impact of time delays, unplanned activities (e.g., outbreak response), and programmatic cost overruns.  It should also outline a process for updating the investment case, particularly as the current path(s) change(s) (e.g., if one of the alternatives becomes the new current or status quo path).  Effective use of the investment case as a living document will require periodic iteration, and this will require an ongoing commitment to keep it updated.  We anticipate that the process may need to include creation of an independent oversight committee or monitoring board (i.e., separate from the organizations responsible for management discussed in 4.3).
5.   Conclusions The investment case should provide a set of conclusions and include any recommendations about preferred alternatives with respect to any of the attributes (i.e., it should identify the set of “best” options that exist based on the quantitative analyses and on specific qualitative factors).  The conclusions should reflect and support the deliberations by stakeholders (not preclude or preempt them) and make all assumptions clear such that stakeholders can debate and iterate on the alternatives with the objective of reaching global consensus on and commitment to the preferred path.
End Matter The investment case should include a list of references, a list of acronyms, and a glossary that defines key terms and any technical appendices needed to provide details about the data and models used for its quantitative analyses, which should provide enough detail that technical readers could replicate the analyses.  The technical appendices may also include details about the qualitative analyses of the health systems, equity, or other issues.
Table 1: Content for an investment case for globally-coordinated management of infectious diseases.