A Cost-Effectiveness Analysis of Population-Level Dental Caries Prevention Strategies in US Children.

OBJECTIVE: To improve oral health disparities and outcomes among US children impacted by dental caries, there is a need to understand the cost-effectiveness of a targeted, risk-based versus universal-based approach for caries prevention. METHODS: Health and economic outcomes were simulated in a cohort of 50,000 US children aged 1-18 years, comparing current practice (CP) to risk-based-prevention (RBP) and prevention-for-all (PFA) strategies using health care sector and limited societal perspectives. Prevention included biannual oral health exams and fluoride varnish application, and one-time dental sealant placement. The primary outcome is the cost-effectiveness ratio (ICER), defined as the additional cost per quality-adjusted life year (QALY) gained when comparing each strategy to the next least costly one. RESULTS: For RBP compared to CP, the ICER was US$83,000/QALY from the health care sector perspective; for PFA compared to RBP the ICER was US$154,000/QALY. Using a limited societal perspective that includes caregiver time spent attending dental or medical setting visits, RBP compared to CP yielded a ratio of $119,000/QALY and PFA compared to RBP was $235,000/QALY. Results were most sensitive to changes in the probability of pain from an episode of dental caries, costs for prevention and restoration, and the loss in health-related quality of life due to dental caries pain. Scenario analyses evaluating a reduced intensity of prevention services yielded lower ICERs. CONCLUSION: Using a risk-based approach that identifies and targets children at increased risk for dental caries to guide the delivery of prevention services represents an economic value similar to other pediatric prevention programs.

Recommendations for Emerging Good Practice and Future Research in Relation to Family and Caregiver Health Spillovers in Health Economic Evaluations: A Report of the SHEER Task Force.

BACKGROUND: Omission of family and caregiver health spillovers from the economic evaluation of healthcare interventions remains common practice. When reported, a high degree of methodological inconsistency in incorporating spillovers has been observed. AIM: To promote emerging good practice, this paper from the Spillovers in Health Economic Evaluation and Research (SHEER) task force aims to provide guidance on the incorporation of family and caregiver health spillovers in cost-effectiveness and cost-utility analysis. SHEER also seeks to inform the basis for a spillover research agenda and future practice. METHODS: A modified nominal group technique was used to reach consensus on a set of recommendations, representative of the views of participating subject-matter experts. Through the structured discussions of the group, as well as on the basis of evidence identified during a review process, recommendations were proposed and voted upon, with voting being held over two rounds. RESULTS: This report describes 11 consensus recommendations for emerging good practice. SHEER advocates for the incorporation of health spillovers into analyses conducted from a healthcare/health payer perspective, and more generally inclusive perspectives such as a societal perspective. Where possible, spillovers related to displaced/foregone activities should be considered, as should the distributional consequences of inclusion. Time horizons ought to be sufficient to capture all relevant impacts. Currently, the collection of primary spillover data is preferred and clear justification should be provided when using secondary data. Transparency and consistency when reporting on the incorporation of health spillovers are crucial. In addition, given that the evidence base relating to health spillovers remains limited and requires much development, 12 avenues for future research are proposed. CONCLUSIONS: Consideration of health spillovers in economic evaluations has been called for by researchers and policymakers alike. Accordingly, it is hoped that the consensus recommendations of SHEER will motivate more widespread incorporation of health spillovers into analyses. The developing nature of spillover research necessitates that this guidance be viewed as an initial roadmap, rather than a strict checklist. Moreover, there is a need for balance between consistency in approach, where valuable in a decision making context, and variation in application, to reflect differing decision maker perspectives and to support innovation.

Cost-effectiveness of routine annual influenza vaccination by age and risk status.

BACKGROUND: The epidemiology of circulating seasonal influenza strains changed following the 2009 pandemic influenza A(H1N1). A universal influenza vaccination recommendation has been implemented and new vaccine types have become available post-2009. The objective of this study was to evaluate the cost-effectiveness of routine annual influenza vaccination in the context of this new evidence. METHODS: A state transition simulation model was constructed to estimate the health and economic outcomes of influenza vaccination compared to no vaccination for hypothetical US cohorts stratified by age and risk status. Model input parameters were derived from multiple sources, including post-2009 vaccine effectiveness data from the US Flu Vaccine Effectiveness Network. The analysis used societal and healthcare sector perspectives and a one-year time horizon, except permanent outcomes were also included. The primary outcome was the incremental cost-effectiveness ratio (ICER) in dollars per quality-adjusted life years (QALYs) gained. RESULTS: Compared to no vaccination, vaccination yielded ICERs lower than $95,000/QALY for all age and risk groups, except for non-high-risk adults 18-49 years ($194,000/QALY). Vaccination was cost-saving for adults ≥50 years at higher risk for influenza-related complications. Results were most sensitive to changes in the probability of influenza illness. Performing the analysis from the healthcare sector perspective, excluding vaccination time costs, delivering vaccinations in lower-cost settings, and including productivity losses improved the cost-effectiveness of vaccination. Sensitivity analysis revealed that vaccination remains below $100,000/QALY for older persons ≥65 years at vaccine effectiveness estimates as low as 4 %. CONCLUSIONS: Cost-effectiveness of influenza vaccination varied by age and risk status and was less than $95,000/QALY for all subgroups, except for non-high-risk working-age adults. Results were sensitive to the probability of influenza illness and vaccination was more favorable under certain scenarios. Vaccination for higher risk subgroups resulted in ICERs below $100,000/QALY even at low levels of vaccine effectiveness or circulating virus.

Preexisting Financial Hardship Among Caregivers of Hospitalized Children.

This cross-sectional study examines preexisting financial hardship among caregivers of hospitalized children.

Developing Criteria for Health Economic Quality Evaluation Tool.

OBJECTIVES: Because existing publication guidelines and checklists have limitations when used to assess the quality of cost-effectiveness analysis, we developed a novel quality assessment tool for cost-effectiveness analyses, differentiating methods and reporting quality and incorporating the relative importance of different quality attributes. METHODS: We defined 15 quality domains from a scoping review and identified 72 methods and reporting quality attributes (36 each). After designing a best-worst scaling survey, we fielded an online survey to researchers and practitioners to estimate the relative importance of the attributes in February 2021. We analyzed the survey data using a sequential conditional logit model. The final tool included 48 quality attributes deemed most important for assessing methods and reporting quality (24 each), accompanied by a free and web-based scoring system. RESULTS: A total of 524 participants completed the methodology section, and 372 completed both methodology and reporting sections. Quality attributes pertaining to the "modeling" and "data inputs and evidence synthesis" domains were deemed most important for methods quality, including "structure of the model reflects the underlying condition and intervention's impact" and "model validation is conducted." Quality attributes pertaining to "modeling" and "Intervention/comparator(s)" domains were considered most important for reporting quality, including "model descriptions are detailed enough for replication." Despite its growing prominence, "equity considerations" were not deemed as important as other quality attributes. CONCLUSIONS: The Criteria for Health Economic Quality Evaluation tool allows users to differentiate methods and reporting as well as quantifies the relative importance of quality attributes. Alongside other considerations, it could help assess and improve the quality of cost-effectiveness evidence to inform value-based decisions.

Eliciting Trade-Offs Between Equity and Efficiency: A Methodological Scoping Review.

OBJECTIVES: To identify differences in the approaches and results of studies that elicit equity-efficiency trade-offs that can inform equity-informative cost-effectiveness analysis for healthcare resource allocation. METHODS: We searched Ovid (Medline), EconLit, and Scopus prior to June 25, 2021. Inclusion criteria were: (1) peer-reviewed or (2) gray literature; (3) published in English; (4) survey-based; (5) parameterized a social welfare function to quantify inequality aversion or (6) elicited a trade-off in equity and efficiency characteristics of health interventions. Exclusion criteria were: (1) studies that did not conduct a trade-off or (2) theoretical studies. We abstracted details on study methods, results, and limitations. Studies were grouped by following approach: (1) social welfare function or (2) preference ranking and distributional weighting. We described findings separately for each approach category. RESULTS: Seventy-seven papers were included, 28 parameterized social welfare functions and 49 were classified as preference ranking and distributional weighting. Study methods were heterogeneous. Studies were conducted across 29 countries. Sample sizes and composition, survey methods and question framing varied. Preferences for equity were mixed. Across both approach categories: 39 studies were classified as clear evidence of inequality aversion; 33 found mixed evidence; and 4 had no evidence of aversion. Evidence of between and within-study heterogeneity was found. Preferences for equity may differ by gender, profession, political ideology, income, and education. CONCLUSIONS: Substantial variability in study methods limit the direct comparability of findings and their use in equity-informed cost-effectiveness analysis. Future researches using representative samples that explore within and between country heterogeneity is needed.

Cost-Effectiveness Analysis of Vaccination With Recombinant Zoster Vaccine Among Hematopoietic Cell Transplant Recipients and Persons With Other Immunocompromising Conditions Aged 19 to 49 Years.

OBJECTIVES: This study aimed to estimate the cost-effectiveness of the use of recombinant zoster vaccine (RZV) (Shingrix), which protects against herpes zoster (HZ), among immunocompromised adults aged 19 to 49 years, as a contribution to deliberations of the Advisory Committee on Immunization Practices. METHODS: Hematopoietic cell transplant (HCT) recipients experience a high incidence of HZ, and the efficacy of RZV in preventing HZ has been studied in clinical trials. The cost-effectiveness model calculated incremental cost-effectiveness ratios that compared vaccination with RZV with a no vaccination strategy among adults aged 19 to 49 years. Costs and outcomes were calculated until age 50 years using the healthcare sector perspective and summarized as cost per quality-adjusted life-year (QALY) gained. The base case represents HCT recipients, with scenario analyses representing persons with other immunocompromising conditions, including hematologic malignancies, human immunodeficiency virus, and autoimmune and inflammatory conditions. Uncertainty was investigated using univariate, multivariate, and probabilistic sensitivity analyses. RESULTS: Base-case results indicated vaccination with RZV would avert approximately 35% of HZ episodes and complications, while saving approximately 11% of net costs. Compared with no vaccination, vaccination of HCT recipients with RZV generated cost-savings (ie, lower costs and improved health) in the base case and in 81% of simulations in the probabilistic analysis. In scenario analyses, vaccination cost US dollar ($) 9500/QALY among patients with hematologic malignancies, $79 000/QALY among persons living with human immunodeficiency virus, and $208 000/QALY among persons with selected autoimmune and inflammatory conditions. CONCLUSIONS: Generally favorable economic estimates supported recommendations for vaccination of immunocompromised adults with RZV to prevent episodes of HZ and related complications.

Economic Evaluation Design within the HEAL Prevention Cooperative.

The rapid rise in opioid misuse, disorder, and opioid-involved deaths among older adolescents and young adults is an urgent public health problem. Prevention is a vital part of the nation's response to the opioid crisis, yet preventive interventions for those at risk for opioid misuse and opioid use disorder are scarce. In 2019, the National Institutes of Health (NIH) launched the Preventing Opioid Use Disorder in Older Adolescents and Young Adults cooperative as part of its broader Helping to End Addiction Long-term (HEAL) Initiative ( https://heal.nih.gov/ ). The HEAL Prevention Cooperative (HPC) includes ten research projects funded with the goal of developing effective prevention interventions across various settings (e.g., community, health care, juvenile justice, school) for older adolescent and young adults at risk for opioid misuse and opioid use disorder (OUD). An important component of the HPC is the inclusion of an economic evaluation by nine of these research projects that will provide information on the costs, cost-effectiveness, and sustainability of these interventions. The HPC economic evaluation is integrated into each research project's overall design with start-up costs and ongoing delivery costs collected prospectively using an activity-based costing approach. The primary objectives of the economic evaluation are to estimate the intervention implementation costs to providers, estimate the cost-effectiveness of each intervention for reducing opioid misuse initiation and escalation among youth, and use simulation modeling to estimate the budget impact of broader implementation of the interventions within the various settings over multiple years. The HPC offers an extraordinary opportunity to generate economic evidence for substance use prevention programming, providing policy makers and providers with critical information on the investments needed to start-up prevention interventions, as well as the cost-effectiveness of these interventions relative to alternatives. These data will help demonstrate the valuable role that prevention can play in combating the opioid crisis.

Projected risks and health benefits of vaccination against herpes zoster and related complications in US adults.

The Advisory Committee on Immunization Practices (ACIP) recommends recombinant zoster vaccine (RZV) to prevent against herpes zoster (HZ) and related complications in immunocompetent adults ≥50 y and immunocompromised adults ≥19 y. In 2019, a statistical safety signal for Guillain-Barré syndrome (GBS) following RZV was identified using data from the Vaccine Safety Datalink (VSD). Subsequently, the U.S. Food and Drug Administration (FDA), the Centers for Disease Control and Prevention (CDC), and collaborators undertook additional analyses using Centers for Medicare & Medicaid Services (CMS) Medicare data to further investigate the potential risk of GBS following RZV. Concurrently, epidemiologic data suggested a potentially elevated risk of GBS following HZ in U.S. adults. Using data from these sources and a published simulation model, this study evaluated the health benefits and risks associated with vaccinating immunocompetent adults ≥50 y with RZV compared to no vaccination. In the base case analysis, RZV vaccination averted 43,000-63,000 cases of HZ, including GBS complications, per million vaccinated per 10-y age cohort compared to 3-6 additional cases of GBS projected following RZV per million vaccinated in the same population. This analysis highlights the projected health benefits of RZV vaccination compared to the relatively low potential risk of GBS following RZV.

What's the Cost? Measuring the Economic Impact of Pediatric Sepsis.

Sepsis, life-threatening organ dysfunction secondary to infection, hospitalizes nearly 75,000 children each year in the United States. Most children survive sepsis. However, there is increasing recognition of the longer-term consequences of pediatric sepsis hospitalization on both the child and their family, including medical, psychosocial, and financial impacts. Here, we describe family spillover effects (the impact of illness on caregivers) of pediatric sepsis, why measurement of family spillover effects is important, and the ways in which family spillover effects can be measured.

Newborn Screening and Treatment of Phenylketonuria: Projected Health Outcomes and Cost-Effectiveness.

The objective of this study was to evaluate the cost-effectiveness of newborn screening and treatment for phenylketonuria (PKU) in the context of new data on adherence to recommended diet treatment and a newly available drug treatment (sapropterin dihydrochloride). A computer simulation model was developed to project outcomes for a hypothetical cohort of newborns with PKU. Four strategies were compared: (1) clinical identification (CI) with diet treatment; (2) newborn screening (NBS) with diet treatment; (3) CI with diet and medication (sapropterin dihydrochloride); and (4) NBS with diet and medication. Data sources included published literature, primary data, and expert opinion. From a societal perspective, newborn screening with diet treatment had an incremental cost-effectiveness ratio of $6400/QALY compared to clinical identification with diet treatment. Adding medication to NBS with diet treatment resulted in an incremental cost-effectiveness ratio of more than $16,000,000/QALY. Uncertainty analyses did not substantially alter the cost-effectiveness results. Newborn screening for PKU with diet treatment yields a cost-effectiveness ratio lower than many other recommended childhood prevention programs even if adherence is lower than previously assumed. Adding medication yields cost-effectiveness results unlikely to be considered favorable. Future research should consider conditions under which sapropterin dihydrochloride would be more economically attractive.

Incorporating Cascade Effects of Genetic Testing in Economic Evaluation: A Scoping Review of Methodological Challenges.

Cascade genetic testing is indicated for family members of individuals testing positive on a genetic test, and is particularly relevant for child health because of their vulnerability and the long-term health and economic implications. Cascade testing has patient- and health system-level implications; however cascade costs and health effects are not routinely considered in economic evaluation. The methodological challenges associated with incorporating cascade effects in economic evaluation require examination. The purpose of this scoping review was to identify published economic evaluations that considered cascade genetic testing. Citation databases were searched for English-language economic evaluations reporting on cascade genetic testing. Nineteen publications were included. In four, genetic testing was used to identify new index patients-cascade effects were also considered; thirteen assessed cascade genetic testing strategies for the identification of at-risk relatives; and two calculated the costs of cascade genetic testing as a secondary objective. Methodological challenges associated with incorporating cascade effects in economic evaluation are related to study design, costing, measurement and valuation of health outcomes, and modeling. As health economic studies may currently be underestimating both the cost and health benefits attributable to genetic technologies through omission of cascade effects, development of methods to address these difficulties is required.

Cost-effectiveness of pediatric norovirus vaccination in daycare settings.

OBJECTIVE: Noroviruses are the leading cause of acute gastroenteritis in the United States and outbreaks frequently occur in daycare settings. Results of norovirus vaccine trials have been promising, however there are open questions as to whether vaccination of daycare children would be cost-effective. We investigated the incremental cost-effectiveness of a hypothetical norovirus vaccination for children in daycare settings compared to no vaccination. METHODS: We conducted a model-based cost-effectiveness analysis using a disease transmission model of children attending daycare. Vaccination with a 90% coverage rate in addition to the observed standard of care (exclusion of symptomatic children from daycare) was compared to the observed standard of care. The main outcomes measures were infections and deaths averted, quality-adjusted life years (QALYs), costs, and incremental cost-effectiveness ratio (ICER). Cost-effectiveness was analyzed from a societal perspective, including medical costs to children as well as productivity losses of parents, over a two-year time horizon. Data sources included outbreak surveillance data and published literature. RESULTS: A 50% efficacious norovirus vaccine averts 571.83 norovirus cases and 0.003 norovirus-related deaths per 10,000 children compared to the observed standard of care. A $200 norovirus vaccine that is 50% efficacious has a net cost increase of $178.10 per child and 0.025 more QALYs, resulting in an ICER of $7,028/QALY. Based on the probabilistic sensitivity analysis, we estimated that a $200 vaccination with 50% efficacy was 94.0% likely to be cost-effective at a willingness-to-pay of $100,000/QALY threshold and 95.3% likely at a $150,000/QALY threshold. CONCLUSION: Due to the large disease burden associated with norovirus, it is likely that vaccinating children in daycares could be cost-effective, even with modest vaccine efficacy and a high per-child cost of vaccination. Norovirus vaccination of children in daycare has a cost-effectiveness ratio similar to other commonly recommended childhood vaccines.

Assessing the Appropriateness of the EQ-5D for Duchenne Muscular Dystrophy: A Patient-Centered Study.

BACKGROUND: Duchenne muscular dystrophy is a rare degenerative neuromuscular disorder with pediatric onset. Recent approvals in Duchenne have placed attention on the economic evaluation in pricing and reimbursement decisions across a range of rare conditions. We sought to assess the appropriateness of the EQ-5D, a common measure of generic health state utility, for use among patients and caregivers affected by Duchenne. METHODS: An international, cross-sectional sample of adults with Duchenne and caregivers reported patient health status using self- or proxy-reported EQ-5D-3L. Appropriateness was assessed across 6 domains of concern raised by stakeholders in Duchenne. These concerns were that the EQ-5D/EQ-VAS would not capture meaningful differences in health status, correlate with disease-specific measures, reflect real health status, exhibit face validity, be accurately interpreted, and be low burden. We evaluated these concerns by comparing EQ-5D index score and EQ-VAS scores to other condition-specific functional measures and open- and closed-ended questions. RESULTS: In total, 263 participants (74% response) completed the survey, 24% of whom were adult patients. Most participants lived in the United States or United Kingdom (58%). Patient age ranged from 1 to 48 y. EQ-5D index was higher in ambulatory than nonambulatory patients (0.60 v. 0.30, P < 0.001) and was negatively correlated with upper limb impairment (r = 0.61, P < 0.001). Three-quarters of respondents agreed that EQ-5D measured real health status (74%). Most respondents interpreted EQ-VAS anchors of best and worst imaginable health as full health (61%) and death/near death (58%). Respondents indicated the EQ-5D was easy to understand (86%) and answer (71%). CONCLUSIONS: Contrary to anecdotal concerns, we found support for the appropriateness of EQ-5D to assess health status in Duchenne. While other measures may be more sensitive to specific outcomes in Duchenne, there may be some value in results using the EQ-5D measure.

Examining Equity Effects of Health Interventions in Cost-Effectiveness Analysis: A Systematic Review.

OBJECTIVE: This systematic review aims to catalogue and describe published applications of equity-informative cost-effectiveness analysis (CEAs). METHODS: Following PRISMA guidelines, we searched Medline for English-language, peer-reviewed CEAs published on or before August 2019. We included CEAs that evaluated 2 or more alternatives; explicitly mentioned equity as a consideration or decision-making principle; and applied an equity-informative CEA method to analyze or examine at least 1 equity criterion in an applied CEA. We extracted data on selected characteristics and analyzed reporting quality using the CHEERS checklist. RESULTS: Fifty-four articles identified through a search and bibliography reviews met the inclusion criteria. All articles were published on or after 2010, with 80% published after 2015. Most studies evaluated primary prevention interventions in disease areas such as cancer, infectious diseases, and cardiovascular disease. Equity impact analysis alone was the most common equity-informative CEA (56%), followed by equity impact analysis with financial protection effects (30%). At least 11 different equity criteria have been used in equity-informative CEAs; socioeconomic status and race/ethnicity were used most frequently. Seventy-eight percent of studies reported finding "greater value" in an intervention after examining its distributional effects. CONCLUSION: The number of equity-informative CEAs is increasing, and the wide range of equity criteria, diseases, interventions, settings, and populations represented suggests that broad application of these methods is feasible but will require further refinement. Inclusion of equity into CEAs may shift the value of evaluated interventions and can provide crucial additional information for decision makers.

Health and economic outcomes of newborn screening for infantile-onset Pompe disease.

PURPOSE: To estimate health and economic outcomes associated with newborn screening (NBS) for infantile-onset Pompe disease in the United States. METHODS: A decision analytic microsimulation model simulated health and economic outcomes of a birth cohort of 4 million children in the United States. Universal NBS and treatment was compared with clinical identification and treatment of infantile-onset Pompe disease. Main outcomes were projected cases identified, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) over the life course. RESULTS: Universal NBS for Pompe disease and confirmatory testing was estimated to cost an additional $26 million annually. Additional medication costs associated with earlier treatment initiation were $181 million; however, $8 million in medical care costs for other services were averted due to delayed disease progression. Infants with screened and treated infantile-onset Pompe disease experienced an average lifetime increase of 11.66 QALYs compared with clinical detection. The ICER was $379,000/QALY from a societal perspective and $408,000/QALY from the health-care perspective. Results were sensitive to the cost of enzyme replacement therapy. CONCLUSION: Newborn screening for Pompe disease results in substantial health gains for individuals with infantile-onset Pompe disease, but with additional costs.

Vaccine Hesitancy and Concerns About Vaccine Safety and Effectiveness in Shanghai, China.

INTRODUCTION: Rapidly urbanizing communities in middle-income countries could be sources of vaccine hesitancy, and may create hot spots of low vaccination coverage. This study characterizes vaccine hesitancy in Shanghai and identifies disparities in vaccine safety and efficacy concerns by residency status-a marker for recent migration into the city. METHODS: Parents of children aged ≤18 years from immunization clinics in Shanghai were enrolled in summer 2019, with the data analyzed during winter 2019-2020. The paper questionnaire used the Parental Attitudes towards Childhood Vaccines scale, which included questions about vaccine safety and efficacy concerns. The primary independent variable was residency-whether an individual was a Shanghai local or a recent migrant (i.e., non-local). Linear regression models assessed the relationship between residency and vaccine safety and efficacy concerns. RESULTS: Among 1,021 participants, 65.4% had local residency, and the remainder were urban non-locals (13.1%) or rural non-locals (21.5%). A majority of parents expressed concerns about vaccine side effects (73.8%), vaccine safety (63.9%), and vaccine effectiveness (52.4%). Compared with locals, rural non-locals were more concerned about vaccine side effects (ß=0.26, 95% CI=0.07, 0.46), vaccine safety (ß=0.42, 95% CI=0.19, 0.65), and vaccine effectiveness (ß=0.37, 95% CI=0.16, 0.58). CONCLUSIONS: Differences in vaccine hesitancy by residency could lead to geographical and sociodemographic disparities in vaccination coverage and outbreaks of vaccine-preventable disease. SUPPLEMENT INFORMATION: This article is part of a supplement entitled Global Vaccination Equity, which is sponsored by the Global Institute for Vaccine Equity at the University of Michigan School of Public Health.

Cost-effectiveness of the Adaptive Implementation of Effective Programs Trial (ADEPT): approaches to adopting implementation strategies.

BACKGROUND: Theory-based methods to support the uptake of evidence-based practices (EBPs) are critical to improving mental health outcomes. Implementation strategy costs can be substantial, and few have been rigorously evaluated. The purpose of this study is to conduct a cost-effectiveness analysis to identify the most cost-effective approach to deploying implementation strategies to enhance the uptake of Life Goals, a mental health EBP. METHODS: We used data from a previously conducted randomized trial to compare the cost-effectiveness of Replicating Effective Programs (REP) combined with external and/or internal facilitation among sites non-responsive to REP. REP is a low-level strategy that includes EBP packaging, training, and technical assistance. External facilitation (EF) involves external expert support, and internal facilitation (IF) augments EF with protected time for internal staff to support EBP implementation. We developed a decision tree to assess 1-year costs and outcomes for four implementation strategies: (1) REP only, (2) REP+EF, (3) REP+EF add IF if needed, (4) REP+EF/IF. The analysis used a 1-year time horizon and assumed a health payer perspective. Our outcome was quality-adjusted life years (QALYs). The economic outcome was the incremental cost-effectiveness ratio (ICER). We conducted deterministic and probabilistic sensitivity analysis (PSA). RESULTS: Our results indicate that REP+EF add IF is the most cost-effective option with an ICER of $593/QALY. The REP+EF/IF and REP+EF only conditions are dominated (i.e., more expensive and less effective than comparators). One-way sensitivity analyses indicate that results are sensitive to utilities for REP+EF and REP+EF add IF. The PSA results indicate that REP+EF, add IF is the optimal strategy in 30% of iterations at the threshold of $100,000/QALY. CONCLUSIONS: Our results suggest that the most cost-effective implementation support begins with a less intensive, less costly strategy initially and increases as needed to enhance EBP uptake. Using this approach, implementation support resources can be judiciously allocated to those clinics that would most benefit. Our results were not robust to changes in the utility measure. Research is needed that incorporates robust and relevant utilities in implementation studies to determine the most cost-effective strategies. This study advances economic evaluation of implementation by assessing costs and utilities across multiple implementation strategy combinations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02151331 , 05/30/2014.