Prevalence of Gastric Precursor Lesions in Countries With Differential Gastric Cancer Burden: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: The prevalence of precursor lesions for gastric cancer (GC) and the differential burden between countries of varying GC risk is not well-understood. We conducted a systematic review and meta-analysis to estimate the global prevalence of precursor lesions. METHODS: We estimated the prevalence of atrophic gastritis (AG), gastric intestinal metaplasia (IM), and dysplasia in regions with low, medium, and high GC incidence. Because IM is an advanced manifestation of AG, we assessed the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. Prevalence was sub-stratified by Helicobacter pylori infection, symptomatology, and period (<2000, 2000-2010, and >2010). RESULTS: Among the 582 articles that underwent full-text review, 166 studies met inclusion criteria. The global prevalence estimates of AG, IM, and dysplasia were 25.4%, 16.2%, and 2.0%, respectively, on the basis of 126 studies that reported the prevalence of less advanced precursors, regardless of the presence of more advanced lesions. The prevalence of all precursor lesions was higher in high and medium compared with low GC incidence countries (P < .01). Prevalence of AG and IM was significantly higher among H pylori-infected individuals (P < .01) but not statistically different between symptomatic and asymptomatic individuals (P > .17). All precursors demonstrated a secular decrease in prevalence over time. CONCLUSIONS: Gastric precursor lesions have differences in prevalence in regions with differential GC incidence and are associated with H pylori infection. Because of the substantial prevalence of precursor lesions in both symptomatic and asymptomatic individuals, symptomatic evaluation may not be sufficient to identify individuals at risk. These estimates provide important insights for tailoring GC prevention strategies.

Logical Inconsistencies in the Health Years in Total and Equal Value of Life-Years Gained.

OBJECTIVES: This study aimed to assess whether recently proposed alternatives to the quality-adjusted life-year (QALY), intended to address concerns about discrimination, are suitable for informing resource allocation decisions. METHODS: We consider 2 alternatives to the QALY: the health years in total (HYT), recently proposed by Basu et al, and the equal value of life-years gained (evLYG), currently used by the Institute for Clinical and Economic Review. For completeness we also consider unweighted life-years (LYs). Using a hypothetical example comparing 3 mutually exclusive treatment options, we consider how calculations are performed under each approach and whether the resulting rankings are logically consistent. We also explore some further challenges that arise from the unique properties of the HYT approach. RESULTS: The HYT and evLYG approaches can result in logical inconsistencies that do not arise under the QALY or LY approaches. HYT can violate the independence of irrelevant alternatives axiom, whereas the evLYG can produce an unstable ranking of treatment options. HYT have additional issues, including an implausible assumption that the utilities associated with health-related quality of life and LYs are "separable," and a consideration of "counterfactual" health-related quality of life for patients who are dead. CONCLUSIONS: The HYT and evLYG approaches can result in logically inconsistent decisions. We recommend that decision makers avoid these approaches and that the logical consistency of any approaches proposed in future be thoroughly explored before considering their use in practice.

The Effect of Nationwide Organized Cancer Screening Programs on Gastric Cancer Mortality: A Synthetic Control Study.

BACKGROUND & AIMS: Nationwide organized gastric cancer (GC) screening programs have been running for decades in South Korea and Japan. This study conducted a quasi-experimental analysis to assess the population impact of these programs on GC mortality. METHODS: We used the flexible synthetic control method (SCM) to estimate the effect of the screening programs on age-standardized GC mortality and other upper gastrointestinal (UGI) diseases (esophageal cancer and peptic ulcer) among people aged ≥40 years. World Health Organization mortality data and country-level covariates from the World Bank and the Global Burden of Diseases study were used for the analyses. We compared postintervention trends in outcome with the counterfactual trend of the synthetic control and estimated average postintervention rate ratios (RRs) with associated 95% confidence intervals (CIs). A series of sensitivity analyses were conducted. RESULTS: The preintervention fits were acceptable for the analyses of South Korea and Japan's GC mortality but poor for Japan's other UGI disease mortality. The average postintervention RRs were 0.83 (95% CI, 0.71-0.96) for GC mortality and 0.72 (95% CI, 0.57-0.90) for other UGI disease mortality in South Korea. The RR reached 0.59 by the 15th year after the initiation of nationwide screening. For Japan, the average RRs were 0.97 (95% CI, 0.88-1.07) for GC mortality and 0.93 (95% CI, 0.68-1.28) for other UGI disease mortality. Sensitivity analysis reveals the result for Japan may potentially be biased. CONCLUSIONS: South Korea's nationwide GC screening has apparent benefits, whereas the Japanese program's effectiveness is uncertain. The experiences of South Korea and Japan could serve as a reference for other countries.

We need to talk about values: a proposed framework for the articulation of normative reasoning in health technology assessment.

It is acknowledged that health technology assessment (HTA) is an inherently value-based activity that makes use of normative reasoning alongside empirical evidence. But the language used to conceptualise and articulate HTA's normative aspects is demonstrably unnuanced, imprecise, and inconsistently employed, undermining transparency and preventing proper scrutiny of the rationales on which decisions are based. This paper - developed through a cross-disciplinary collaboration of 24 researchers with expertise in healthcare priority-setting - seeks to address this problem by offering a clear definition of key terms and distinguishing between the types of normative commitment invoked during HTA, thus providing a novel conceptual framework for the articulation of reasoning. Through application to a hypothetical case, it is illustrated how this framework can operate as a practical tool through which HTA practitioners and policymakers can enhance the transparency and coherence of their decision-making, while enabling others to hold them more easily to account. The framework is offered as a starting point for further discussion amongst those with a desire to enhance the legitimacy and fairness of HTA by facilitating practical public reasoning, in which decisions are made on behalf of the public, in public view, through a chain of reasoning that withstands ethical scrutiny.

Development and validation of colorectal cancer risk prediction tools: A comparison of models.

BACKGROUND: Identification of individuals at elevated risk can improve cancer screening programmes by permitting risk-adjusted screening intensities. Previous work introduced a prognostic model using sex, age and two preceding faecal haemoglobin concentrations to predict the risk of colorectal cancer (CRC) in the next screening round. Using data of 3 screening rounds, this model attained an area under the receiver-operating-characteristic curve (AUC) of 0.78 for predicting advanced neoplasia (AN). We validated this existing logistic regression (LR) model and attempted to improve it by applying a more flexible machine-learning approach. METHODS: We trained an existing LR and a newly developed random forest (RF) model using updated data from 219,257 third-round participants of the Dutch CRC screening programme until 2018. For both models, we performed two separate out-of-sample validations using 1,137,599 third-round participants after 2018 and 192,793 fourth-round participants from 2020 onwards. We evaluated the AUC and relative risks of the predicted high-risk groups for the outcomes AN and CRC. RESULTS: For third-round participants after 2018, the AUC for predicting AN was 0.77 (95% CI: 0.76-0.77) using LR and 0.77 (95% CI: 0.77-0.77) using RF. For fourth-round participants, the AUCs were 0.73 (95% CI: 0.72-0.74) and 0.73 (95% CI: 0.72-0.74) for the LR and RF models, respectively. For both models, the 5% with the highest predicted risk had a 7-fold risk of AN compared to average, whereas the lowest 80% had a risk below the population average for third-round participants. CONCLUSION: The LR is a valid risk prediction method in stool-based screening programmes. Although predictive performance declined marginally, the LR model still effectively predicted risk in subsequent screening rounds. An RF did not improve CRC risk prediction compared to an LR, probably due to the limited number of available explanatory variables. The LR remains the preferred prediction tool because of its interpretability.

Appropriateness of strategy comparisons in cost-effectiveness analyses of infant pneumococcal vaccination: a systematic review.

OBJECTIVES: Cost-effectiveness analysis (CEA) is the standard framework for informing the efficient allocation of scarce healthcare resources. The importance of considering all relevant intervention strategies and appropriate incremental comparisons have both long been recognized in CEA. Failure to apply methods correctly can lead to suboptimal policies. Our objective is to assess if CEAs of infant pneumococcal vaccination apply appropriate methods with respect to the completeness of strategies assessed and incremental comparisons between them. METHODS: We conducted a systematic search of the PubMed, Scopus, Embase, and Web of Science databases and performed a comparative analysis of the retrieved pneumococcal vaccination CEAs. We checked the appropriateness of the incremental analyses by attempting to replicate the published incremental cost-effectiveness (CE) ratios from the reported costs and health effects. RESULTS: Our search returned twenty-nine eligible articles. Most studies failed to recognize one or more intervention strategies (n = 21). Incremental comparisons were questionable in four CEAs and insufficient reporting of cost and health effect estimates was identified in three studies. Overall, we only found four studies that made appropriate comparisons between all strategies. Lastly, study findings appear to be strongly associated with manufacturer sponsorship. CONCLUSIONS: We found considerable scope for improvement regarding strategy comparison in the infant pneumococcal vaccination literature. To prevent overestimation of the CE of new vaccines, we urge greater adherence to existing guidelines recommending that all available strategies are evaluated to capture relevant comparators for CE evaluation. Closer adherence to existing guidelines will generate better evidence, leading to more effective vaccination policies.

A Simple Cost-Effectiveness Model of Screening: An Open-Source Teaching and Research Tool Coded in R.

Applied cost-effectiveness analysis models are an important tool for assessing health and economic effects of healthcare interventions but are not best suited for illustrating methods. Our objective is to provide a simple, open-source model for the simulation of disease-screening cost-effectiveness for teaching and research purposes. We introduce our model and provide an initial application to examine changes to the efficiency frontier as input parameters vary and to demonstrate face validity. We described a vectorised, discrete-event simulation of screening in R with an Excel interface to define parameters and inspect principal results. An R Shiny app permits dynamic interpretation of simulation outputs. An example with 8161 screening strategies illustrates the cost and effectiveness of varying the disease sojourn time, treatment effectiveness, and test performance characteristics and costs on screening policies. Many of our findings are intuitive and straightforward, such as a reduction in screening costs leading to decreased overall costs and improved cost-effectiveness. Others are less obvious and depend on whether we consider gross outcomes or those net to no screening. For instance, enhanced treatment of symptomatic disease increases gross effectiveness, but reduces the net effectiveness and cost-effectiveness of screening. A lengthening of the preclinical sojourn time has ambiguous effects relative to no screening, as cost-effectiveness improves for some strategies but deteriorates for others. Our simple model offers an accessible platform for methods research and teaching. We hope it will serve as a public good and promote an intuitive understanding of the cost-effectiveness of screening.

A Systematic Review of Cost-Effectiveness Analyses of Colorectal Cancer Screening in Europe: Have Studies Included Optimal Screening Intensities?

OBJECTIVE: To assess the range of strategies analysed in European cost-effectiveness analyses (CEAs) of colorectal cancer (CRC) screening with respect to the screening intervals, age ranges and test cut-offs used to define positivity, to examine how this might influence what strategies are found to be optimal, and compare them with the current screening policies with a focus on the screening interval. METHODS: We searched PubMed, Web of Science and Scopus for peer-reviewed, model-based CEAs of CRC screening. We included studies on average-risk European populations using the guaiac faecal occult blood test (gFOBT) or faecal immunochemical test (FIT). We adapted Drummond's ten-point checklist to appraise study quality. RESULTS: We included 39 studies that met the inclusion criteria. Biennial screening was the most frequently used interval which was analysed in 37 studies. Annual screening was assessed in 13 studies, all of which found it optimally cost-effective. Despite this, 25 of 26 European stool-based programmes use biennial screening. Many CEAs did not vary the age range, but the 14 that did generally found broader ranges optimal. Only 11 studies considered alternative FIT cut-offs, 9 of which found lower cut-offs superior. Conflicts between current policy and CEA evidence are less clear regarding age ranges and cut-offs. CONCLUSIONS: The existing CEA evidence indicates that the widely adopted biennial frequency of stool-based testing in Europe is suboptimal. It is likely that many more lives could be saved throughout Europe if programmes could be offered with more intensive annual screening.

Targeted combination therapies in oncology: Challenging regulatory frameworks designed for monotherapies in Europe.

The pharmaceutical value chain, including clinical trials, pricing, access, and reimbursement, is designed for classical monotherapies. Although there has been a paradigm shift that increases the relevance of targeted combination therapies (TCTs), regulation and common practice have been slow to adapt. We explored access to 23 TCTs for advanced melanoma and lung cancer as reported by 19 specialists from 17 leading cancer institutions in nine European countries. We find heterogeneous patient access to TCTs between countries, differences in country-specific regulations, and differences in the clinical practice of melanoma and lung cancer. Regulation that is better tailored to the context of combinational therapies can increase equity in access across Europe and promote an evidence-based and authorized use of combinations.

Expanding health technology assessment towards broader value: Ireland as a case study.

Healthcare innovations often represent important improvements in population welfare, but at what cost, and to whom? Health technology assessment (HTA) is a multidisciplinary process to inform resource allocation. HTA is conventionally anchored on health maximization as the only relevant output of health services. If we accept the proposition that health technologies can generate value outside the healthcare system, resource allocation decisions could be suboptimal from a societal perspective. Incorporating "broader value" in HTA as derived from social values and patient experience could provide a richer evaluative space for informing resource allocation decisions. This article considers how HTA is practiced and what its current context implies for adopting "broader value" to evaluating health technologies. Methodological challenges are highlighted, as is a future research agenda. Ireland serves as an example of a healthcare system that both has an explicit role for HTA and is evolving under a current program of reform to offer universal, single-tier access to public services. There are various ways in which HTA processes could move beyond health, including considering the processes of care delivery and/or expanding the evaluative space to some broader concept of well-being. Methods to facilitate the latter exist, but their adaptation to HTA is still emerging. We recommend a multi-stakeholder working group to develop and advance an international agenda for HTA that captures welfare/benefit beyond health.

A model-based analysis of the health impacts of COVID-19 disruptions to primary cervical screening by time since last screen for current and future disruptions.

We evaluated how temporary disruptions to primary cervical cancer (CC) screening services may differentially impact women due to heterogeneity in their screening history and test modality. We used three CC models to project the short- and long-term health impacts assuming an underlying primary screening frequency (i.e., 1, 3, 5, or 10 yearly) under three alternative COVID-19-related screening disruption scenarios (i.e., 1-, 2-, or 5-year delay) versus no delay in the context of both cytology-based and human papillomavirus (HPV)-based screening. Models projected a relative increase in symptomatically detected cancer cases during a 1-year delay period that was 38% higher (Policy1-Cervix), 80% higher (Harvard), and 170% higher (MISCAN-Cervix) for underscreened women whose last cytology screen was 5 years prior to the disruption period compared with guidelines-compliant women (i.e., last screen 3 years prior to disruption). Over a woman's lifetime, temporary COVID-19-related delays had less impact on lifetime risk of developing CC than screening frequency and test modality; however, CC risks increased disproportionately the longer time had elapsed since a woman's last screen at the time of the disruption. Excess risks for a given delay period were generally lower for HPV-based screeners than for cytology-based screeners. Our independent models predicted that the main drivers of CC risk were screening frequency and screening modality, and the overall impact of disruptions from the pandemic on CC outcomes may be small. However, screening disruptions disproportionately affect underscreened women, underpinning the importance of reaching such women as a critical area of focus, regardless of temporary disruptions.

Cost-Effectiveness Analyses of Lung Cancer Screening Using Low-Dose Computed Tomography: A Systematic Review Assessing Strategy Comparison and Risk Stratification.

OBJECTIVES: Our first study objective was to assess the range of lung cancer screening intervals compared within cost-effectiveness analyses (CEAs) of low-dose computed tomography (LDCT) and to examine the implications for the strategies identified as optimally cost effective; the second objective was to examine if and how risk subgroup-specific policies were considered. METHODS: PubMed, Embase and Web of Science were searched for model-based CEAs of LDCT lung screening. The retrieved studies were assessed to examine if the analyses considered sufficient strategy variation to permit incremental estimation of cost effectiveness. Regarding risk selection, we examined if analyses considered alternative risk strata in separate analyses or as alternative risk-based eligibility criteria for screening. RESULTS: The search identified 33 eligible CEAs, 23 of which only considered one screening frequency. Of the 10 analyses considering multiple screening intervals, only 4 included intervals longer than 2 years. Within the 10 studies considering multiple intervals, the optimal policy choice would differ in 5 if biennial intervals or longer had not been considered. Nineteen studies conducted risk subgroup analyses, 12 of which assumed that subgroup-specific policies were possible and 7 of which assumed that a common screening policy applies to all those screened. CONCLUSIONS: The comparison of multiple strategies is recognised as good practice in CEA when seeking optimal policies. Studies that do include multiple intervals indicate that screening intervals longer than 1 year can be relevant. The omission of intervals of 2 years or longer from CEAs of LDCT screening could lead to the adoption of sub-optimal policies. There also is scope for greater consideration of risk-stratified policies which tailor screening intensity to estimated disease risk. Policy makers should take care when interpreting current evidence before implementing lung screening.

Health impacts of COVID-19 disruptions to primary cervical screening by time since last screen: A model-based analysis for current and future disruptions.

Background: We evaluated how temporary disruptions to primary cervical cancer (CC) screening services may differentially impact women due to heterogeneity in their screening history and test modality. Methods: We used three CC models to project the short- and long-term health impacts assuming an underlying primary screening frequency (i.e., 1, 3, 5, or 10 yearly) under three alternative COVID-19-related screening disruption scenarios (i.e., 1-, 2- or 5-year delay) versus no delay, in the context of both cytology-based and HPV-based screening. Results: Models projected a relative increase in symptomatically-detected cancer cases during a 1-year delay period that was 38% higher (Policy1-Cervix), 80% higher (Harvard) and 170% higher (MISCAN-Cervix) for under-screened women whose last cytology screen was 5 years prior to the disruption period compared with guidelines-compliant women (i.e., last screen three years prior to disruption). Over a woman's lifetime, temporary COVID-19-related delays had less impact on lifetime risk of developing CC than screening frequency and test modality; however, CC risks increased disproportionately the longer time had elapsed since a woman's last screen at the time of the disruption. Excess risks for a given delay period were generally lower for HPV-based screeners than for cytology-based screeners. Conclusions: Our independent models predicted that the main drivers of CC risk were screening frequency and screening modality, and the overall impact of disruptions from the pandemic on CC outcomes may be small. However, screening disruptions disproportionately affect under-screened women, underpinning the importance of reaching such women as a critical area of focus, regardless of temporary disruptions. Funding: This study was supported by funding from the National Cancer Institute (U01CA199334). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Megan A Smith receives salary support from the National Health and Medical Research Council, Australia (APP1159491) and Cancer Institute NSW (ECF181561). Matejka Rebolj is funded by Cancer Research UK (reference: C8162/A27047). James O'Mahony is funded by Ireland's Health Research Board (EIA2017054). Karen Canfell receives salary support from the National Health and Medical Research Council, Australia (APP1194679). Emily A. Burger receives salary support from the Norwegian Cancer Society.

Colorectal Cancer Screening within Colonoscopy Capacity Constraints: Can FIT-Based Programs Save More Lives by Trading off More Sensitive Test Cutoffs against Longer Screening Intervals?

Introduction. Colorectal cancer (CRC) prevention programs using fecal immunochemical testing (FIT) in screening rely on colonoscopy for secondary and surveillance testing. Colonoscopy capacity is an important constraint. Some European programs lack sufficient capacity to provide optimal screening intensity regarding age ranges, intervals, and FIT cutoffs. It is currently unclear how to optimize programs within colonoscopy capacity constraints. Design. Microsimulation modeling, using the MISCAN-Colon model, was used to determine if more effective CRC screening programs can be identified within constrained colonoscopy capacity. A total of 525 strategies were modeled and compared, varying 3 key screening parameters: screening intervals, age ranges, and FIT cutoffs, including previously unevaluated 4- and 5-year screening intervals (using a lifetime horizon and 100% adherence). Results were compared with the policy decisions taken in Ireland to provide CRC screening within available colonoscopy capacity. Outcomes estimated net costs, quality-adjusted life-years (QALYs), and required colonoscopies. The optimal strategies within finite colonoscopy capacity constraints were identified. Results. Combining a reduced FIT cutoff of 10 µg Hb/g, an extended screening interval of 4 y and an age range of 60-72 y requires 6% fewer colonoscopies, reduces net costs by 23% while preventing 15% more CRC deaths and saving 16% more QALYs relative to a strategy (FIT 40 µg Hb/g, 2-yearly, 60-70 year) approximating current policy. Conclusion. Previously overlooked longer screening intervals may optimize cancer prevention with finite colonoscopy capacity constraints. Changes could save lives, reduce costs, and relieve colonoscopy capacity pressures. These findings are relevant to CRC screening programs across Europe that employ FIT-based testing, which face colonoscopy capacity constraints.

Variation of prescription drug prices in community pharmacies: A national cross-sectional study.

Background; There is evidence of significant variation of prescription drug prices in community pharmacies in several countries. Prescription drugs are a major source of expenditure for patients. High prices can lead to cost-related non-adherence and adverse health outcomes. Objective; This study's aim was to establish the variation and availability of prescription drug prices in community pharmacies in Ireland. Methods; Using a cross-sectional design, prices were sought in community pharmacies using phone, email and website enquiries. A purposive sample of 12 prescription drugs was included. The prescription drugs were selected from the top 100 medications by dispensing frequency in 2017 on Ireland's main state drug scheme. For each pharmacy, the price was checked for three drugs only. Researchers sought to contact 1,500 pharmacies by phone and 320 by email, as well as consult the website of 370 pharmacies. Results; In total, 1,529 pharmacies responded to queries, 1,362 by telephone and 167 by email. Overall, 88.5% (N = 1,353) of pharmacies who answered queries, provided prices. For each drug, the average price quoted to researchers was higher than the price paid by the state for patients who can access subsidised medicines. The ratio of 90th to 10th percentile prices ranged from 1.3 to 2.0 for the twelve drugs. A Welch's t-test found that for nine of the 12 drugs, the price was significantly higher (p < .05) for chain pharmacies compared to independent pharmacies. Conclusions; Evidence was found of significant price variation in community pharmacies. There was also evidence that some community pharmacies were not following regulatory guidance on drug pricing transparency. Policy measures such as mandated price transparency, or fixed prescription drug prices could help address these price issues.

Cost-effectiveness evidence on approved cancer drugs in Ireland: the limits of data availability and implications for public accountability.

BACKGROUND: We surveyed evidence published by Ireland's National Centre for Pharmacoeconomics (NCPE) on the cost-effectiveness of cancer drugs approved for funding within the Irish public healthcare system. The purpose is threefold: to assess the completeness and clarity of publicly available cost-effectiveness data of such therapies; to provide summary estimates of that data; to consider the implications of constraints on data availability for accountability regarding healthcare resource allocation. METHODS: The National Cancer Control Programme lists 91 drug-indication pairs approved between June 2012 and July 2020. Records were retrieved from the NCPE website for each drug-indication pair, including, where available, health technology assessment (HTA) summary reports. We assessed what cost-effectiveness data regarding approved interventions is available, aggregated it and considered the consequences of reporting constraints. RESULTS: Among the 91 drug-indication pairs 61 were reimbursed following full HTA, 22 after a rapid review process and 8 have no corresponding NCPE record. Of the 61 where an HTA report was available, 41 presented costs and quality-adjusted life-year (QALY) estimates of the interventions compared. Cost estimates and corresponding incremental cost-effectiveness ratios (ICERs) are based on prices on application for reimbursement. Reimbursed prices are not published. Aggregating over the drug-indication pairs for which data is available, we find a mean incremental health gain of 0.85 QALY and an aggregate ICER of €100,295/QALY, which exceeds Ireland's cost-effectiveness threshold of €45,000/QALY. CONCLUSION: Reimbursement applications by pharmaceutical manufacturers for cancer drugs typically exceed Ireland's cost-effectiveness threshold, often by a considerable margin. On aggregate, the additional total net cost of new drugs relative to current treatments needs to be more than halved for the prices sought on application to be justified for reimbursement. Commercial confidentiality regarding prices and cost-effectiveness upon reimbursement compromises accountability regarding the fair and efficient allocation of scarce healthcare resources.

Risk Stratification in Cost-Effectiveness Analyses of Cancer Screening: Intervention Eligibility, Strategy Choice, and Optimality.

INTRODUCTION: There is increasing interest in risk-stratified approaches to cancer screening in cost-effectiveness analysis (CEA). Current CEA practice regarding risk stratification is heterogeneous and guidance on the best approach is lacking. This article suggests how stratification in CEA can be improved. METHODS: I use a simple example of a hypothetical screening intervention with 3 potential recipient risk strata. The screening intervention has 6 alternative intensities, each with different costs and effects, all of which vary between strata. I consider a series of alternative stratification approaches, demonstrating the consequences for estimated costs, effects, and the choice of optimal strategy. I supplement this analysis with applied examples from the literature. RESULTS: Adopting the same screening policy for all strata yields the least efficient strategies, where efficiency is understood as the volume of net health benefit generated across a range of cost-effectiveness threshold values. Basic stratification that withholds screening from lower-risk strata while adopting a common strategy for those screened increases efficiency. Greatest efficiency is achieved when different strata receive separate strategies. While complete optimization can be achieved within a single analysis by considering all possible policy combinations, the resulting number of strategy combinations may be inconveniently large. Optimization with separate strata-specific analyses is simpler and more transparent. Despite this, there can be good reasons to simulate all strata together in a single analysis. CONCLUSIONS: If the benefits of risk stratification are to be fully realized, policy makers need to consider the extent to which stratification is feasible, and modelers need to simulate those choices adequately. It is hoped this analysis will clarify those policy and modeling choices and therefore lead to improved population health outcomes.

Revision of Ireland's Cost-Effectiveness Threshold: New State-Industry Drug Pricing Deal Should Adequately Reflect Opportunity Costs.

Ireland's cost-effectiveness threshold is currently €45,000 per quality-adjusted life-year (QALY). It has previously been determined by periodic agreements between the State and a pharma industry lobby body. A new deal is due in July 2021 and it is therefore timely to re-examine Ireland's threshold, how it is set and transparency around adherence to it. Previous research has noted a series of problems with the threshold, including that it is likely too high relative to the opportunity cost of unmet need within Ireland's health system. This means reimbursement at the threshold may do net harm to population health. The high threshold may also mean the Irish health system is failing to satisfy existing legislation on healthcare resource allocation. Recent COVID-19-related pressures on healthcare capacity and public spending appear to increase the urgency for an evidence-based revision of threshold to better reflect opportunity costs within the Irish healthcare system. Despite these problems, the prospects for reform of the threshold do not appear strong as the political and institutional incentives may favour the status quo. At the very least, the State should provide greater transparency regarding how the threshold is set and adhered to. A potential reform for consideration in the longer run could include a partial abandonment of thresholds in favour of an auction process to achieve the lowest cost per QALY from new drug interventions.