The use of cost-effectiveness analysis for health benefit package design - should countries follow a sectoral, incremental or hybrid approach?

BACKGROUND: Countries around the world are increasingly rethinking the design of their health benefit package to achieve universal health coverage. Countries can periodically revise their packages on the basis of sectoral cost-effectiveness analyses, i.e. by evaluating a broad set of services against a 'doing nothing' scenario using a budget constraint. Alternatively, they can use incremental cost-effectiveness analyses, i.e. to evaluate specific services against current practice using a threshold. In addition, countries may employ hybrid approaches which combines elements of sectoral and incremental cost-effectiveness analysis - a country may e.g. not evaluate the comprehensive set of all services but rather relatively small sets of services targeting a certain condition. However, there is little practical guidance for countries as to which kind of approach they should follow. METHODS: The present study was based on expert consultation. We refined the typology of approaches of cost-effectiveness analysis for benefit package design, identified factors that should be considered in the choice of approach, and developed recommendations. We reached consensus among experts over the course of several review rounds. RESULTS: Sectoral cost-effectiveness analysis is especially suited in contexts with large allocative inefficiencies in current service provision and can, in theory, realize large efficiency gains. However, it may be challenging to implement a comprehensive redesign of the package in practice. Incremental cost-effectiveness analysis is especially relevant in contexts where specific new services may impact the sustainability of the health system. It may potentially support efficiency improvement, but its focus has typically been on new services while existing inefficiencies remain unchallenged. The use of hybrid approach may be a way forward to address the strengths and weaknesses of sectoral and incremental analysis areas. Such analysis may be especially useful to target disease areas with suspected high inefficiencies in service provision, and would then make good use of the available research capacity and be politically rewarding. However, disease-specific analyses bear the risk of not addressing resource allocation inefficiencies across disease areas. CONCLUSIONS: Countries should carefully select their approach of cost-effectiveness analyses for benefit package design, based on their decision-making context.

Obg and Membrane Depolarization Are Part of a Microbial Bet-Hedging Strategy that Leads to Antibiotic Tolerance.

Within bacterial populations, a small fraction of persister cells is transiently capable of surviving exposure to lethal doses of antibiotics. As a bet-hedging strategy, persistence levels are determined both by stochastic induction and by environmental stimuli called responsive diversification. Little is known about the mechanisms that link the low frequency of persisters to environmental signals. Our results support a central role for the conserved GTPase Obg in determining persistence in Escherichia coli in response to nutrient starvation. Obg-mediated persistence requires the stringent response alarmone (p)ppGpp and proceeds through transcriptional control of the hokB-sokB type I toxin-antitoxin module. In individual cells, increased Obg levels induce HokB expression, which in turn results in a collapse of the membrane potential, leading to dormancy. Obg also controls persistence in Pseudomonas aeruginosa and thus constitutes a conserved regulator of antibiotic tolerance. Combined, our findings signify an important step toward unraveling shared genetic mechanisms underlying persistence.

Validation of Lung EpiCheck, a novel methylation-based blood assay, for the detection of lung cancer in European and Chinese high-risk individuals.

AIM: Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples. METHODS: A case-control European training set (n=102 lung cancer cases, n=265 controls) was used to define the panel and algorithm. Two cut-offs were selected, low cut-off (LCO) for high sensitivity and high cut-off (HCO) for high specificity. The performance was validated in case-control European and Chinese validation sets (cases/controls 179/137 and 30/15, respectively). RESULTS: The European and Chinese validation sets achieved AUCs of 0.882 and 0.899, respectively. The sensitivities/specificities with LCO were 87.2%/64.2% and 76.7%/93.3%, and with HCO they were 74.3%/90.5% and 56.7%/100.0%, respectively. Stage I nonsmall cell lung cancer (NSCLC) sensitivity in European and Chinese samples with LCO was 78.4% and 70.0% and with HCO was 62.2% and 30.0%, respectively. Small cell lung cancer (SCLC) was represented only in the European set and sensitivities with LCO and HCO were 100.0% and 93.3%, respectively. In multivariable analyses of the European validation set, the assay's ability to predict lung cancer was independent of established risk factors (age, smoking, COPD), and overall AUC was 0.942. CONCLUSIONS: Lung EpiCheck demonstrated strong performance in lung cancer prediction in case-control European and Chinese samples, detecting high proportions of early-stage NSCLC and SCLC and significantly improving predictive accuracy when added to established risk factors. Prospective studies are required to confirm these findings. Utilising such a simple and inexpensive blood test has the potential to improve compliance and broaden access to screening for at-risk populations.

Increasing the Legitimacy of Tough Choices in Healthcare Reimbursement: Approach and Results of a Citizen Forum in The Netherlands.

BACKGROUND: Some studies in the Netherlands have gauged public views on principles for healthcare priority setting, but they fall short of comprehensively explaining the public disapproval of several recent reimbursement decisions. OBJECTIVE: To obtain insight into citizens' preferences and identify the criteria they would propose for decisions pertaining to the benefits package of basic health insurance. METHODS: Twenty-four Dutch citizens were selected for participation in a Citizen Forum, which involved 3 weekends. Deliberations took place in small groups and in plenary, guided by 2 moderators, on the basis of 8 preselected case studies, which participants later compared and prioritized under the premise that not all treatments can or need to be reimbursed. Participants received opportunities to inform themselves through written brochures and live interactions with 3 experts. RESULTS: The Citizen Forum identified 16 criteria for inclusion or exclusion of treatments in the benefits package; they relate to the condition (2 criteria), treatment (11 criteria), and individual characteristics of those affected by the condition (3 criteria). In most case studies, it was a combination of criteria that determined whether or not participants favored inclusion of the treatment under consideration in the benefits package. Participants differed in their opinion about the relative importance of criteria, and they had difficulty in operationalizing and trading off criteria to provide a recommendation. CONCLUSIONS: Informed citizens are prepared to make and, to a certain extent, capable of making reasoned choices about the reimbursement of health services. They realize that choices are both necessary and possible. Broad public support and understanding for making tough choices regarding the benefits package of basic health insurance is not automatic: it requires an investment.

Multicriteria Decision Analysis to Support Health Technology Assessment Agencies: Benefits, Limitations, and the Way Forward.

OBJECTIVE: Recent years have witnessed an increased interest in the use of multicriteria decision analysis (MCDA) to support health technology assessment (HTA) agencies for setting healthcare priorities. However, its implementation to date has been criticized for being "entirely mechanistic," ignoring opportunity costs, and not following best practice guidelines. This article provides guidance on the use of MCDA in this context. METHODS: The present study was based on a systematic review and consensus development. We developed a typology of MCDA studies and good implementation practice. We reviewed 36 studies over the period 1990 to 2018 on their compliance with good practice and developed recommendations. We reached consensus among authors over the course of several review rounds. RESULTS: We identified 3 MCDA study types: qualitative MCDA, quantitative MCDA, and MCDA with decision rules. The types perform differently in terms of quality, consistency, and transparency of recommendations on healthcare priorities. We advise HTA agencies to always include a deliberative component. Agencies should, at a minimum, undertake qualitative MCDA. The use of quantitative MCDA has additional benefits but also poses design challenges. MCDA with decision rules, used by HTA agencies in The Netherlands and the United Kingdom and typically referred to as structured deliberation, has the potential to further improve the formulation of recommendations but has not yet been subjected to broad experimentation and evaluation. CONCLUSION: MCDA holds large potential to support HTA agencies in setting healthcare priorities, but its implementation needs to be improved.

Translating international HIV treatment guidelines into local priorities in Indonesia.

OBJECTIVE: International guidelines recommend countries to expand antiretroviral therapy (ART) to all HIV-infected individuals and establish local-level priorities in relation to other treatment, prevention and mitigation interventions through fair processes. However, no practical guidance is provided for such priority-setting processes. Evidence-informed deliberative processes (EDPs) fill this gap and combine stakeholder deliberation to incorporate relevant social values with rational decision-making informed by evidence on these values. This study reports on the first-time implementation and evaluation of an EDP in HIV control, organised to support the AIDS Commission in West Java province, Indonesia, in the development of its strategic plan for 2014-2018. METHODS: Under the responsibility of the provincial AIDS Commission, an EDP was implemented to select priority interventions using six steps: (i) situational analysis; (ii) formation of a multistakeholder Consultation Panel; (iii) selection of criteria; (iv) identification and assessment of interventions' performance; (v) deliberation; and (vi) selection of funding and implementing institutions. An independent researcher conducted in-depth interviews (n = 21) with panel members to evaluate the process. RESULTS: The Consultation Panel included 23 stakeholders. They identified 50 interventions and these were evaluated against four criteria: impact on the epidemic, stigma reduction, cost-effectiveness and universal coverage. After a deliberative discussion, the Consultation Panel prioritised a combination of several treatment, prevention and mitigation interventions. CONCLUSION: The EDP improved both stakeholder involvement and the evidence base for the strategic planning process. EDPs fill an important gap which international guidelines and current tools for strategic planning in HIV control leave unaddressed.

Evidence for scaling up HIV treatment in sub-Saharan Africa: A call for incorporating health system constraints.

Jan Hontelez and colleagues argue that the cost-effectiveness studies of HIV treatment scale-up need to include health system constraints to be more informative.

Value Assessment Frameworks for HTA Agencies: The Organization of Evidence-Informed Deliberative Processes.

Priority setting in health care has been long recognized as an intrinsically complex and value-laden process. Yet, health technology assessment agencies (HTAs) presently employ value assessment frameworks that are ill fitted to capture the range and diversity of stakeholder values and thereby risk compromising the legitimacy of their recommendations. We propose "evidence-informed deliberative processes" as an alternative framework with the aim to enhance this legitimacy. This framework integrates two increasingly popular and complementary frameworks for priority setting: multicriteria decision analysis and accountability for reasonableness. Evidence-informed deliberative processes are, on one hand, based on early, continued stakeholder deliberation to learn about the importance of relevant social values. On the other hand, they are based on rational decision-making through evidence-informed evaluation of the identified values. The framework has important implications for how HTA agencies should ideally organize their processes. First, HTA agencies should take the responsibility of organizing stakeholder involvement. Second, agencies are advised to integrate their assessment and appraisal phases, allowing for the timely collection of evidence on values that are considered relevant. Third, HTA agencies should subject their decision-making criteria to public scrutiny. Fourth, agencies are advised to use a checklist of potentially relevant criteria and to provide argumentation for how each criterion affected the recommendation. Fifth, HTA agencies must publish their argumentation and install options for appeal. The framework should not be considered a blueprint for HTA agencies but rather an aspirational goal-agencies can take incremental steps toward achieving this goal.

National Immunization Program Decision Making Using the CAPACITI Decision-Support Tool: User Feedback from Indonesia and Ethiopia.

To ensure that limited domestic resources are invested in the most effective interventions, immunization programs in low- and middle-income countries (LMICs) must prioritize a growing number of new vaccines while considering opportunities to optimize the vaccine portfolio, as well as other components of the health system. There is a strong impetus for immunization decision-making to engage and coordinate various stakeholders across the health system in prioritization. To address this, national immunization program decision-makers in LMICs collaborated with WHO to structure deliberation among stakeholders and document an evidence-based, context-specific, and transparent process for prioritization or selection among multiple vaccination products, services, or strategies. The output of this effort is the Country-led Assessment for Prioritization on Immunization (CAPACITI) decision-support tool, which supports using multiple criteria and stakeholder perspectives to evaluate trade-offs affecting health interventions, taking into account variable data quality. Here, we describe the user feedback from Indonesia and Ethiopia, two initial countries that piloted the CAPACITI decision-support tool, highlighting enabling and constraining factors. Potential immunization program benefits and lessons learned are also summarized for consideration in other settings.

Assessing Global Evidence on Cost-Effectiveness to Inform Development of Pakistan's Essential Package of Health Services.

BACKGROUND: Countries designing a health benefit package (HBP) to support progress towards universal health coverage (UHC) require robust cost-effectiveness evidence. This paper reports on Pakistan's approach to assessing the applicability of global cost-effectiveness evidence to country context as part of a HBP design process. METHODS: A seven-step process was developed and implemented with Disease Control Priority 3 (DCP3) project partners to assess the applicability of global incremental cost-effectiveness ratios (ICERs) to Pakistan. First, the scope of the interventions to be assessed was defined and an independent, interdisciplinary team was formed. Second, the team familiarized itself with intervention descriptions. Third, the team identified studies from the Tufts Medical School Global Health Cost-Effectiveness Analysis (GH-CEA) registry. Fourth, the team applied specific knock-out criteria to match identified studies to local intervention descriptions. Matches were then cross-checked across reviewers and further selection was made where there were multiple ICER matches. Sixth, a quality scoring system was applied to ICER values. Finally, a database was created containing all the ICER results with a justification for each decision, which was made available to decision-makers during HBP deliberation. RESULTS: We found that less than 50% of the interventions in DCP3 could be supported with evidence of cost-effectiveness applicable to the country context. Out of 78 ICERs identified as applicable to Pakistan from the Tufts GH-CEA registry, only 20 ICERs were exact matches of the DCP3 Pakistan intervention descriptions and 58 were partial matches. CONCLUSION: This paper presents the first attempt globally to use the main public GH-CEA database to estimate cost-effectiveness in the context of HBPs at a country level. This approach is a useful learning for all countries trying to develop essential packages informed by the global database on ICERs, and it will support the design of future evidence and further development of methods.

Costing Interventions for Developing an Essential Package of Health Services: Application of a Rapid Method and Results From Pakistan.

BACKGROUND: The Federal Ministry of National Health Services, Regulations and Coordination (MNHSR&C) in Pakistan has committed to progress towards universal health coverage (UHC) by 2030 by providing an Essential Package of Health Services (EPHS). Starting in 2019, the Disease Control Priorities 3rd edition (DCP3) evidence framework was used to guide the development of Pakistan's EPHS. In this paper, we describe the methods and results of a rapid costing approach used to inform the EPHS design process. METHODS: A total of 167 unit costs were calculated through a context-specific, normative, ingredients-based, and bottom-up economic costing approach. Costs were constructed by determining resource use from descriptions provided by MNHSR&C and validated by technical experts. Price data from publicly available sources were used. Deterministic univariate sensitivity analyses were carried out. RESULTS: Unit costs ranged from 2019 US$ 0.27 to 2019 US$ 1478. Interventions in the cancer package of services had the highest average cost (2019 US$ 837) while interventions in the environmental package of services had the lowest (2019 US$ 0.68). Cost drivers varied by platform; the two largest drivers were drug regimens and surgery-related costs. Sensitivity analyses suggest our results are not sensitive to changes in staff salary but are sensitive to changes in medicine pricing. CONCLUSION: We estimated a large number of context-specific unit costs, over a six-month period, demonstrating a rapid costing method suitable for EPHS design.

Addressing the UHC Challenge Using the Disease Control Priorities 3 Approach: Lessons Learned and an Overview of the Pakistan Experience.

BACKGROUND: Pakistan developed its first national Essential Package of Health Services (EPHS) as a key step towards accelerating progress in achieving Universal Health Coverage (UHC). We describe the rationale, aims, the systematic approach followed to EPHS development, methods adopted, outcomes of the process, challenges encountered, and lessons learned. METHODS: EPHS design was led by the Ministry of National Health Services, Regulations & Coordination. The methods adopted were technically guided by the Disease Control Priorities 3 Country Translation project and existing country experience. It followed a participatory and evidence-informed prioritisation and decision-making processes. RESULTS: The full EPHS covers 117 interventions delivered at the community, health centre and first-level hospital platforms at a per capita cost of US$29.7. The EPHS also includes an additional set of 12 population-based interventions at US$0.78 per capita. An immediate implementation package (IIP) of 88 district-level interventions costing US$12.98 per capita will be implemented initially together with the population-based interventions until government health allocations increase to the level required to implement the full EPHS. Interventions delivered at the tertiary care platform were also prioritised and costed at US$6.5 per capita, but they were not included in the district-level package. The national EPHS guided the development of provincial packages using the same evidence-informed process. The government and development partners are in the process of initiating a phased approach to implement the IIP. CONCLUSION: Key ingredients for a successful EPHS design requires a focus on package feasibility and affordability, national ownership and leadership, and solid engagement of national stakeholders and development partners. Major challenges to the transition to implementation are to continue strengthening the national technical capacity, institutionalise priority setting and package design and its revision in ministries of health, address health system gaps and bridge the current gap in financing with the progressive increase in coverage towards 2030.

Costing Interventions for Developing an Essential Package of Health Services: Application of a Rapid Method and Results From Pakistan.

BACKGROUND: The Federal Ministry of National Health Services, Regulations and Coordination (MNHSR&C) in Pakistan has committed to progress towards universal health coverage (UHC) by 2030 by providing an Essential Package of Health Services (EPHS). Starting in 2019, the Disease Control Priorities 3rd edition (DCP3) evidence framework was used to guide the development of Pakistan's EPHS. In this paper, we describe the methods and results of a rapid costing approach used to inform the EPHS design process. METHODS: A total of 167 unit costs were calculated through a context-specific, normative, ingredients-based, and bottom-up economic costing approach. Costs were constructed by determining resource use from descriptions provided by MNHSR&C and validated by technical experts. Price data from publicly available sources were used. Deterministic univariate sensitivity analyses were carried out. RESULTS: Unit costs ranged from 2019 US$ 0.27 to 2019 US$ 1478. Interventions in the cancer package of services had the highest average cost (2019 US$ 837) while interventions in the environmental package of services had the lowest (2019 US$ 0.68). Cost drivers varied by platform; the two largest drivers were drug regimens and surgery-related costs. Sensitivity analyses suggest our results are not sensitive to changes in staff salary but are sensitive to changes in medicine pricing. CONCLUSION: We estimated a large number of context-specific unit costs, over a six-month period, demonstrating a rapid costing method suitable for EPHS design.

The Use of Evidence to Design an Essential Package of Health Services in Pakistan: A Review and Analysis of Prioritisation Decisions at Different Stages of the Appraisal Process.

BACKGROUND: Pakistan embarked on a process of designing an essential package of health services (EPHS) as a pathway towards universal health coverage (UHC). The EPHS design followed an evidence-informed deliberative process; evidence on 170 interventions was introduced along multiple stages of appraisal engaging different stakeholders tasked with prioritising interventions for inclusion. We report on the composition of the package at different stages, analyse trends of prioritised and deprioritised interventions and reflect on the trade-offs made. METHODS: Quantitative evidence on cost-effectiveness, budget impact, and avoidable burden of disease was presented to stakeholders in stages. We recorded which interventions were prioritised and deprioritised at each stage and carried out three analyses: (1) a review of total number of interventions prioritised at each stage, along with associated costs per capita and disability-adjusted life years (DALYs) averted, to understand changes in affordability and efficiency in the package, (2) an analysis of interventions broken down by decision criteria and intervention characteristics to analyse prioritisation trends across different stages, and (3) a description of the trajectory of interventions broken down by current coverage and cost-effectiveness. RESULTS: Value for money generally increased throughout the process, although not uniformly. Stakeholders largely prioritised interventions with low budget impact and those preventing a high burden of disease. Highly cost-effective interventions were also prioritised, but less consistently throughout the stages of the process. Interventions with high current coverage were overwhelmingly prioritised for inclusion. CONCLUSION: Evidence-informed deliberative processes can produce actionable and affordable health benefit packages. While cost-effective interventions are generally preferred, other factors play a role and limit efficiency.

A Practical Guide to Full Value of Vaccine Assessments.

Articulating the wide range of health, social and economic benefits that vaccines offer may help to overcome obstacles in the vaccine development pipeline. A framework to guide the assessment and communication of the value of a vaccine-the Full Value of Vaccine Assessment (FVVA)-has been developed by the WHO. The FVVA framework offers a holistic assessment of the value of vaccines, providing a synthesis of evidence to inform the public health need of a vaccine, describing the supply and demand aspects, its market and its impact from a health, financial and economic perspective. This paper provides a practical guide to how FVVAs are developed and used to support investment in vaccines, ultimately leading to sustained implementation in countries. The FVVA includes a range of elements that can be broadly categorised as synthesis, vaccine development narrative and defining vaccine impact and value. Depending on the features of the disease/vaccine in question, different elements may be emphasised; however, a standardised set of elements is recommended for each FVVA. The FVVA should be developed by an expert group who represent a range of stakeholders, perspectives and geographies and ensure a fair, coherent and evidence-based assessment of vaccine value.

The Use of Evidence-Informed Deliberative Processes for Designing the Essential Package of Health Services in Pakistan.

BACKGROUND: The Disease Control Priorities 3 (DCP3) project provides long-term support to Pakistan in the development and implementation of its universal health coverage essential package of health services (UHC-EPHS). This paper reports on the priority setting process used in the design of the EPHS during the period 2019-2020, employing the framework of evidence-informed deliberative processes (EDPs), a tool for priority setting with the explicit aim of optimising the legitimacy of decision-making in the development of health benefit packages. METHODS: We planned the six steps of the framework during two workshops in the Netherlands with participants from all DCP3 Pakistan partners (October 2019 and February 2020), who implemented these at the country level in Pakistan in 2019 and 2020. Following implementation, we conducted a semi-structured online survey to collect the views of participants in the UHC benefit package design about the prioritisation process. RESULTS: The key steps in the EDP framework were the installation of advisory committees (involving more than 150 members in several Technical Working Groups [TWGs] and a National Advisory Committee [NAC]), definition of decision criteria (effectiveness, cost-effectiveness, avoidable burden of disease, equity, financial risk protection, budget impact, socio-economic impact and feasibility), selection of interventions for evaluation (a total of 170), and assessment and appraisal (across the three dimensions of the UHC cube) of these interventions. Survey respondents were generally positive across several aspects of the priority setting process. CONCLUSION: Despite several challenges, including a partial disruption because of the COVID-19 pandemic, implementation of the priority setting process may have improved the legitimacy of decision-making by involving stakeholders through participation with deliberation, and being evidence-informed and transparent. Important lessons were learned that can be beneficial for other countries designing their own health benefit package such as on the options and limitations of broad stakeholder involvement.

The Use of Evidence to Design an Essential Package of Health Services in Pakistan: A Review and Analysis of Prioritisation Decisions at Different Stages of the Appraisal Process.

BACKGROUND: Pakistan embarked on a process of designing an essential package of health services (EPHS) as a pathway towards universal health coverage (UHC). The EPHS design followed an evidence-informed deliberative process; evidence on 170 interventions was introduced along multiple stages of appraisal engaging different stakeholders tasked with prioritising interventions for inclusion. We report on the composition of the package at different stages, analyse trends of prioritised and deprioritised interventions and reflect on the trade-offs made. METHODS: Quantitative evidence on cost-effectiveness, budget impact, and avoidable burden of disease was presented to stakeholders in stages. We recorded which interventions were prioritised and deprioritised at each stage and carried out three analyses: (1) a review of total number of interventions prioritised at each stage, along with associated costs per capita and disability-adjusted life years (DALYs) averted, to understand changes in affordability and efficiency in the package, (2) an analysis of interventions broken down by decision criteria and intervention characteristics to analyse prioritisation trends across different stages, and (3) a description of the trajectory of interventions broken down by current coverage and cost-effectiveness. RESULTS: Value for money generally increased throughout the process, although not uniformly. Stakeholders largely prioritised interventions with low budget impact and those preventing a high burden of disease. Highly cost-effective interventions were also prioritised, but less consistently throughout the stages of the process. Interventions with high current coverage were overwhelmingly prioritised for inclusion. CONCLUSION: Evidence-informed deliberative processes can produce actionable and affordable health benefit packages. While cost-effective interventions are generally preferred, other factors play a role and limit efficiency.

Tumor- and circulating-free DNA methylation identifies clinically relevant small cell lung cancer subtypes.

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype SCLC from plasma. Using the cfDNA classifier (cfDMC), we demonstrate that SCLC phenotypes can evolve during disease progression, highlighting the need for longitudinal tracking of SCLC during clinical treatment. These data establish that tumor and cfDNA methylation can be used to identify SCLC subtypes and might guide precision SCLC therapy.