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.

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.

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.

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.

The Joint Committee on Vaccination and Immunisation's Advice on Extending Human Papillomavirus Vaccination to Boys: Were Cost-Effectiveness Analysis Guidelines Bent to Achieve a Politically Acceptable Decision?

In July 2018, the UK Minister of Public Health announced that human papillomavirus vaccination would be extended to 12-year-old boys. This decision was informed by updated evidence from the Joint Committee on Vaccination and Immunisation (JCVI) published earlier that month. Vaccination of boys had been found not to be cost-effective in a series of analyses conducted for the JCVI, including the most recent assessment prior to the minister's announcement. These analyses were conducted under the standard methods for cost-effectiveness analysis recommended by the JCVI, which are primarily based on guidelines from the National Institute of Health and Care Excellence. Although the JCVI concluded they were unable to advise extending vaccination on the basis of standard appraisal methods, their most recent round of assessment also considered analyses using nonstandard appraisal methods. In particular, the JCVI noted that vaccination of boys was likely to be cost-effective when a lower discount rate of 1.5% is applied to costs and health effects, as opposed to the 3.5% rate usually employed. The JCVI stated that they were supportive of applying such alternative methods, and on this basis, they would advise extending vaccination to boys. This commentary explains the JCVI's application of nonstandard appraisal methods and considers whether it was justified. We conclude that the JCVI was not justified in applying the lower discount rate. We voice concerns that a willingness to endorse a politically popular intervention may have driven the JCVI to depart from a fair and consistent application of healthcare rationing.

Evaluation of the Effectiveness and Cost-Effectiveness of Personalized Surveillance After Colorectal Adenomatous Polypectomy.

Lifetime risk of developing colorectal cancer is 5%, and 5-year survival at early stage is 92%. Individuals with precancerous lesions removed at primary screening are typically recommended surveillance colonoscopy. Because greater benefits are anticipated for those with higher risk of colorectal cancer, scope for risk-specific surveillance recommendations exists. This review assesses published cost-effectiveness estimates of postpolypectomy surveillance to consider the potential for personalized recommendations by risk group. Meta-analyses of incidence of advanced neoplasia postpolypectomy for low-risk cases were comparable to those without adenoma, with both rates under the lifetime risk of 5%. This group may not benefit from intensive surveillance, which risks unnecessary harm and inefficient use of often scarce colonoscopy capacity. Therefore, greater personalization through deintensified strategies for low-risk individuals could be beneficial. The potential for noninvasive testing, such as fecal immunochemical tests, combined with primary prevention or chemoprevention may reserve colonoscopy for targeted use in personalized risk-stratified surveillance. This review appraised evidence supporting a program of personalized surveillance in patients with colorectal adenoma according to risk group and compared the effectiveness of surveillance colonoscopy with alternative prevention strategies. It assessed trade-offs among costs, benefits, and adverse effects that must be considered in a decision to adopt or reject personalized surveillance.

HIQA's CEA of Breast Screening: Pragmatic Policy Recommendations are Welcome, but ACERs Reported as ICERs are Not.

The Health Information and Quality Authority (HIQA) is Ireland's statutory cost-effectiveness analysis (CEA) agency. It recently published a CEA of screening strategies for women at elevated risk of breast cancer. Although the strategies recommended by HIQA exceed Ireland's cost-effectiveness threshold, they can reasonably be welcomed as a pragmatic response to constraints on disinvestment and are expected to improve screening cost-effectiveness. What is not welcome, however, is HIQA's reporting of average cost-effectiveness ratios (ACERs) as incremental cost-effectiveness ratios (ICERs). The distinction between ACERs and ICERs is well understood in CEA, as is the fact that ICERs not ACERs are the appropriate metric to determine cost-effectiveness. This article critiques HIQA's reporting, considering the implications for the particular case of breast cancer screening and the broader context of consistency of and confidence in CEA as a guide to resource allocation in Ireland. The reporting of ACERs as ICERs is unlikely to be of any great significance in the particular case of screening women at elevated risk of breast cancer, given likely constraints on disinvestment. Despite this, ICERs still need to be reported correctly. If thresholds are exceeded in certain cases, then it is important that decision makers appreciate by how much. More generally, using ACERs in some cases and ICERs in others raises concerns that methods are being applied inconsistently, which risks compromising confidence in CEA in Ireland. As Ireland's statutory CEA authority, HIQA has a special onus of responsibility to ensure established methods are applied correctly.

Beware of Kinked Frontiers: A Systematic Review of the Choice of Comparator Strategies in Cost-Effectiveness Analyses of Human Papillomavirus Testing in Cervical Screening.

OBJECTIVES: To systematically review the choice of comparator strategies in cost-effectiveness analyses (CEAs) of human papillomavirus testing in cervical screening. METHODS: The PubMed, Web of Knowledge, and Scopus databases were searched to identify eligible model-based CEAs of cervical screening programs using human papillomavirus testing. The eligible CEAs were reviewed to investigate what screening strategies were chosen for analysis and how this choice might have influenced estimates of the incremental cost-effectiveness ratio (ICER). Selected examples from the reviewed studies are presented to illustrate how the omission of relevant comparators might influence estimates of screening cost-effectiveness. RESULTS: The search identified 30 eligible CEAs. The omission of relevant comparator strategies appears likely in 18 studies. The ICER estimates in these cases are probably lower than would be estimated had more comparators been included. Five of the 30 studies restricted relevant comparator strategies to sensitivity analyses or other subanalyses not part of the principal base-case analysis. Such exclusion of relevant strategies from the base-case analysis can result in cost-ineffective strategies being identified as cost-effective. CONCLUSIONS: Many of the CEAs reviewed appear to include insufficient comparator strategies. In particular, they omit strategies with relatively long screening intervals. Omitting relevant comparators matters particularly if it leads to the underestimation of ICERs for strategies around the cost-effectiveness threshold because these strategies are the most policy relevant from the CEA perspective. Consequently, such CEAs may not be providing the best possible policy guidance and lead to the mistaken adoption of cost-ineffective screening strategies.

NICE's selective application of differential discounting: ambiguous, inconsistent, and unjustified.

The National Institute for Health and Clinical Excellence (NICE) recently recommended differential discounting of costs and health effects in the economic appraisal of health care interventions in certain circumstances. The recommendation was published in an amendment to NICE's Guide to the Methods of Technology Appraisal. The amendment states that differential discounting should be applied where "treatment effects are both substantial in restoring health and sustained over a very long period (normally at least 30 years)." Renewed interest in differential discounting from NICE is welcome; however, the recommendation's selective application of differential discounting raises a number of concerns. The stated criteria for applying differential discounting are ambiguous. The rationale for the selective application of differential discounting has not been articulated by NICE and is questionable. The selective application of differential discounting leads to several inconsistencies, the most concerning of which is the lower valuation of health gains for those with less than 30 years remaining life expectancy, which can be interpreted as age discrimination. Furthermore, the discount rates chosen by NICE do not appear to be informed by recent advances in the theoretical understanding of differential discounting. NICE's apparent motivation for recommending differential discounting was to ensure a favorable cost-effectiveness ratio for a pediatric oncology drug. While flexibility may be appropriate to allow some interventions that exceed conventional cost-effectiveness thresholds to be adopted, the selective adjustment of appraisal methods is problematic and without justification.

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.

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.

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.

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.

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.

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.