Collaborative model of care between orthopaedics and allied healthcare professionals (CONNACT) in knee osteoarthritis: Effectiveness-implementation hybrid randomized controlled trial of a community-based, multidisciplinary, stratified intervention.

OBJECTIVE: To compare the clinical and cost effectiveness of the Collaborative Model of Care between Orthopaedics and Allied Healthcare Professionals (CONNACT), a community-based, stratified, multidisciplinary intervention consisting of exercise, education, psychological and nutrition delivered through a chronic care model to usual hospital care in adults with knee osteoarthritis (OA). METHODS: Pragmatic, parallel-arm, single-blinded superiority RCT trial. Community-dwelling, ambulant adults with knee OA (Kellgren-Lawrence grade > 1; Knee Injury and OA Outcome Score (KOOS4) ≤75) were enrolled. Primary outcome was KOOS4 at 12-months; secondary outcomes included: quality of life, physical performance measures, symptom satisfaction, psychological outcomes, dietary habits, and global perceived effect. Intention-to-treat analysis using generalized linear model (GLM) and regression modeling were conducted. Economic evaluation through a societal approach was embedded. RESULTS: 110 participants (55 control, 55 intervention) were randomized. No between-group difference found for the primary outcome (MD [95%CI]: -1.86 [-9.11. 5.38]), although both groups demonstrated within-group improvement over 12-months. Among the secondary outcomes, the CONNACT group demonstrated superior dietary change (12 months) and physical performance measures (3 months), and global perceived effect (6 months). While there was no between-group difference in total cost, significant productivity gains (reduced indirect cost) were seen in the CONNACT group. CONCLUSION: CONNACT was not superior to usual care at 1 year. Further efforts are needed to understand the underlying contextual and implementation factors in order to further improve and refine such community-based, stratified care models moving forward. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT03809975. Registered January 18, 2019. https://clinicaltrials.gov/ct2/show/NCT03809975.

Poor Rhinitis and Asthma Control Is Associated With Decreased Health-Related Quality of Life and Utilities: A MASK-air Study.

BACKGROUND: Allergic rhinitis (AR) and asthma may affect health-related quality of life. However, national estimates on the quality of life of patients with AR or asthma are lacking. OBJECTIVE: To provide estimates for utility scores and EuroQoL five-dimension (EQ-5D) visual analog scale (VAS) for patients with AR or asthma. METHODS: We conducted a cross-sectional study using direct patient data from the MASK-air app on European MASK-air users with self-reported AR or asthma. We used a multi-attribute instrument (EQ-5D) to measure quality of life (as utility scores and EQ-5D VAS values). Mean scores were calculated per country and disease control level using multilevel regression models with poststratification, accounting for age and sex biases. RESULTS: We assessed data from 7905 MASK-air users reporting a total of up to 82,737 days. For AR, utilities ranged from 0.86 to 0.99 for good control versus 0.72 to 0.85 for poor control; EQ-5D VAS levels ranged from 78.9 to 87.9 for good control versus 55.3 to 64.2 for poor control. For asthma, utilities ranged from 0.84 to 0.97 for good control versus 0.73 to 0.87 for poor control; EQ-5D VAS levels ranged from 68.4 to 81.5 for good control versus 51.4 to 64.2 for poor control. Poor disease control was associated with a mean loss of 0.14 utilities for both AR and asthma. For the same control levels, AR and asthma were associated with similar utilities and EQ-5D VAS levels. However, lower values were observed for asthma plus AR compared with AR alone. CONCLUSIONS: Poor AR or asthma control are associated with reduced quality of life. The estimates obtained from mobile health data may provide valuable insights for health technology assessment studies.

Measuring healthcare payor management practices in England.

Good management practice in healthcare payors and providers is considered central to ensuring health systems respond to population needs, contain costs, and improve both quality and outcomes. However, the evidence to support this assertion is sparce. While a quantitative link between better management practice and improved patient outcomes has been demonstrated for healthcare providers, no such link has been identified for healthcare payors. The lack of a robust tool to assess the management practices of healthcare payors has impeded such quantitative assessments. We report upon a novel tool developed to measure and assess 11 management practices in all 152 healthcare payors within England's National Health Service in 2010. We have tested the acceptability, reliability and validity of this tool using rigorous analytic methods and present four key findings. First, performance of the tool is strong and comparable to management practice scorecards used in other settings. Second, exploratory factor analysis indicates the tool measures two distinct latent factors of healthcare payor management practice with high internal consistency and reliability. Third, there is evidence of assessment and score validity. Fourth, payor management practice variations are associated with the degree of supervisory oversight. While deploying such a tool is challenging, these results suggest that healthcare payor management practices can be measured and assessed robustly. This could enable governments, and others, to identify how payor management practices influence health system performance and to estimate what health system performance improvements they should expect from interventions designed to improve the management practices of their local healthcare payors.

The Evolving Nature of Health Technology Assessment: A Critical Appraisal of NICE's New Methods Manual.

OBJECTIVES: The National Institute for Health and Care Excellence (NICE) recently completed a review of its methods for health technology assessment, involving a 2-stage public consultation. We appraise proposed methodological changes and analyze key decisions. METHODS: We categorize all changes proposed in the first consultation as "critical," "moderate" or "limited" updates, considering the importance of the topic and the degree of change or the level of reinforcement. Proposals were followed through the review process, for their inclusion, exclusion, or amendment in the second consultation and the new manual. RESULTS: The end-of-life value modifier was replaced with a new "disease severity" modifier and other potential modifiers were rejected. The usefulness of a comprehensive evidence base was emphasized, clarifying when nonrandomized studies can be used, with further guidance on "real-world" evidence developed separately. A greater degree of uncertainty was accepted in circumstances when evidence generation raised challenges, in particular for children, rare diseases, and innovative technologies. For some topics, such as health inequality, discounting, unrelated healthcare costs, and value of information, significant changes were possibly warranted, but NICE decided not to make any revisions at present. CONCLUSION: Most of the changes to NICE's health technology assessment methods are appropriate and modest in impact. Nevertheless, some decisions were not well justified and further research is needed on several topics, including investigation of societal preferences. Ultimately, NICE's role of protecting National Health Services resources for valuable interventions that can contribute toward improving overall population health must be safeguarded, without accepting weaker evidence.

Estimating health care costs at scale in low- and middle-income countries: Mathematical notations and frameworks for the application of cost functions.

Appropriate costing and economic modeling are major factors for the successful scale-up of health interventions. Various cost functions are currently being used to estimate costs of health interventions at scale in low- and middle-income countries (LMICs) potentially resulting in disparate cost projections. The aim of this study is to gain understanding of current methods used and provide guidance to inform the use of cost functions that is fit for purpose. We reviewed seven databases covering the economic and global health literature to identify studies reporting a quantitative analysis of costs informing the projected scale-up of a health intervention in LMICs between 2003 and 2019. Of the 8725 articles identified, 40 met the inclusion criteria. We classified studies according to the type of cost functions applied-accounting or econometric-and described the intended use of cost projections. Based on these findings, we developed new mathematical notations and cost function frameworks for the analysis of healthcare costs at scale in LMICs setting. These notations estimate variable returns to scale in cost projection methods, which is currently ignored in most studies. The frameworks help to balance simplicity versus accuracy and increase the overall transparency in reporting of methods.

Reducing the burden of knee osteoarthritis through community pharmacy: Protocol for a randomised controlled trial of the Knee Care for Arthritis through Pharmacy Service.

INTRODUCTION: Knee osteoarthritis (OA) negatively impacts the health outcomes and equity, social and employment participation, and socio-economic wellbeing of those affected. Little community-based support is offered to people with knee OA in Aotearoa New Zealand. Identifying Maori and non-Maori with knee OA in community pharmacy and providing co-ordinated, evidence- and community-based care may be a scalable, sustainable, equitable, effective and cost-effective approach to improve health and wellbeing. AIM: Assess whether the Knee Care for Arthritis through Pharmacy Service (KneeCAPS) intervention improves knee-related physical function and pain (co-primary outcomes). Secondary aims assess impacts on health-related quality of life, employment participation, medication use, secondary health care utilisation, and relative effectiveness for Maori. METHODS AND ANALYSIS: A pragmatic randomised controlled trial will compare the KneeCAPS intervention to the Pharmaceutical Society of New Zealand Arthritis Fact Sheet and usual care (active control) at 12 months for Maori and non-Maori who have knee OA. Participants will be recruited in community pharmacies. Knee-related physical function will be measured using the function subscale of the Short Form of the Western Ontario and McMaster Universities Osteoarthritis Index. Knee-related pain will be measured using an 11-point numeric pain rating scale. Primary outcome analyses will be conducted on an intention-to-treat basis using linear mixed models. Parallel within-trial health economic analysis and process evaluation will also be conducted. ETHICS AND TRIAL DISSEMINATION: Ethical approval was obtained from the Central Health and Ethics Committee (2022-EXP-11725). The trial is registered with ANZCTR (ACTRN12622000469718). Findings will be submitted for publication and shared with participants.

Guidance on the use of complex systems models for economic evaluations of public health interventions.

To help health economic modelers respond to demands for greater use of complex systems models in public health. To propose identifiable features of such models and support researchers to plan public health modeling projects using these models. A working group of experts in complex systems modeling and economic evaluation was brought together to develop and jointly write guidance for the use of complex systems models for health economic analysis. The content of workshops was informed by a scoping review. A public health complex systems model for economic evaluation is defined as a quantitative, dynamic, non-linear model that incorporates feedback and interactions among model elements, in order to capture emergent outcomes and estimate health, economic and potentially other consequences to inform public policies. The guidance covers: when complex systems modeling is needed; principles for designing a complex systems model; and how to choose an appropriate modeling technique. This paper provides a definition to identify and characterize complex systems models for economic evaluations and proposes guidance on key aspects of the process for health economics analysis. This document will support the development of complex systems models, with impact on public health systems policy and decision making.

Protocol for an OpenSAFELY cohort study collecting patient-reported outcome measures using the TPP Airmid smartphone application and linked big data to quantify the health and economic costs of long COVID (OpenPROMPT).

INTRODUCTION: The impact of long COVID on health-related quality of-life (HRQoL) and productivity is not currently known. It is important to understand who is worst affected by long COVID and the cost to the National Health Service (NHS) and society, so that strategies like booster vaccines can be prioritised to the right people. OpenPROMPT aims to understand the impact of long COVID on HRQoL in adults attending English primary care. METHODS AND ANALYSIS: We will ask people to participate in this cohort study through a smartphone app (Airmid), and completing a series of questionnaires held within the app. Questionnaires will ask about HRQoL, productivity and symptoms of long COVID. Participants will be asked to fill in the questionnaires once a month, for 90 days. Questionnaire responses will be linked, where possible, to participants' existing health records from primary care, secondary care, and COVID testing and vaccination data. Analysis will take place using the OpenSAFELY data platform and will estimate the impact of long COVID on HRQoL, productivity and cost to the NHS. ETHICS AND DISSEMINATION: The Proportionate Review Sub-Committee of the South Central-Berkshire B Research Ethics Committee has reviewed and approved the study and have agreed that we can ask people to take part (22/SC/0198). Our results will provide information to support long-term care, and make recommendations for prevention of long COVID in the future. TRIAL REGISTRATION NUMBER: NCT05552612.

Harnessing People's Lived Experience to Strengthen Health Systems and Support Equitable Musculoskeletal Health Care.

BACKGROUND: Despite the rising burden of musculoskeletal (MSK) problems (MSK conditions, MSK pain, and MSK injury and trauma) in most countries, actions to improve (strengthen) systems for supporting MSK health are often low on the priority list, relative to other noncommunicable diseases. Delivering effective, person-centered and equitable MSK health care requires strengthening systems for health, for example, through policy, financing, service delivery, and workforce initiatives. A critical, but often overlooked component is genuine integration of lived experience perspectives to cocreate care and systems that are responsive to people's needs and contexts. CLINICAL QUESTION: How can cocreation approaches support effective, person-centered and equitable MSK health care? What principles can stakeholders adopt to build responsive health systems? KEY RESULTS: Lived experience perspectives are not systematically integrated in initiatives to strengthen health systems. However, such integration is critical to creating equitable and person-centered health systems that provide care and support healthy populations. Cocreation principles and frameworks can guide processes to strengthen health systems, which must include historically marginalized groups and consider social and environmental contexts as they relate to health. CLINICAL APPLICATION: Clinicians, educators, and policy-makers play a critical role in creating equitable health systems and environments, and driving system reform with people who have lived experience. Genuine cocreation approaches capture diverse economic development (in particular, low-resource settings where health inequities are more prevalent), span the life course and diagnostic categories, are appropriate and/or adapted for the context and setting, and reflect evolving standards and opportunities for MSK health. J Orthop Sports Phys Ther 2023;53(4):1-10. Epub: 12 December 2022. doi:10.2519/jospt.2022.11427.

Extensions of Health Economic Evaluations in R for Microsoft Excel Users: A Tutorial for Incorporating Heterogeneity and Conducting Value of Information Analyses.

Advanced health economic analysis techniques currently performed in Microsoft Excel, such as incorporating heterogeneity, time-dependent transitions and a value of information analysis, can be easily transferred to R. Often the outputs of survival analyses (such as Weibull regression models) will estimate the impacts of correlated patient characteristics on patient outcomes, and are utilised directly as inputs for health economic decision models. This tutorial provides a step-by-step guide of how to conduct such analyses with a Markov model developed in R, and offers a comparison with established analyses performed in Microsoft Excel. This is done through the conversion of a previously published Microsoft Excel case study of a hip replacement surgery cost-effectiveness model. We hope that this paper can act as a facilitator in switching decision models from Microsoft Excel to R for complex health economic analyses, providing open-access code and data, suitable for future adaptation.

Health Economic Evaluation Using Markov Models in R for Microsoft Excel Users: A Tutorial.

A health economic evaluation (HEE) is a comparative analysis of alternative courses of action in terms of both costs and consequences. A cost-effectiveness analysis is a type of HEE that compares an intervention to one or more alternatives by estimating how much it costs to gain an additional unit of health outcome. Cost-effectiveness analyses are commonly performed using Microsoft (MS) Excel. However, there is current interest in using other software that is better suited to more complex problems, methods, and data, as well as improved reproducibility and transparency. That is, it is increasingly important to be able to repeat an analysis of a particular data set and obtain the same results, and access the analysis and results in a clear and comprehensive openly available form. In this tutorial we provide a step-by-step guide on how to implement a mainstay model of HEE, namely a Markov model, in the statistical programming language R. The adoption of R for the purpose of cost-effectiveness analysis is highly dependent on the ability of the health economic modeller to understand, learn, and apply programming-type skills. R is likely to be less familiar than MS Excel for many modellers and so coding a cost-effectiveness model in R can be a large jump. We describe the technical details from the perspective of a MS Excel user to help bridge the gap between software and reduce the learning curve by providing for the first-time side-by-side comparisons of the Markov model example in MS Excel and R.

Cost-Effectiveness of Dapagliflozin as a Treatment for Chronic Kidney Disease: A Health-Economic Analysis of DAPA-CKD.

BACKGROUND AND OBJECTIVES: CKD imposes a significant burden on patients and health care providers, particularly upon reaching kidney failure when patients may require KRT. The Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD) trial demonstrated that dapagliflozin, with standard therapy, reduced CKD progression and KRT requirement. The study objective was to estimate the cost-effectiveness of dapagliflozin for the treatment of CKD from payer perspectives in the United Kingdom, Germany, and Spain. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We constructed a lifetime Markov model to characterize outcomes in patients with CKD on the basis of the DAPA-CKD trial. Health states were defined by eGFR level and KRT type. Direct health care costs and utility values were sourced from published literature and the DAPA-CKD trial, respectively. Costs and benefits were discounted at 3.5% per annum in the United Kingdom and 3% in Germany and Spain. RESULTS: In patients eligible for the DAPA-CKD trial, treatment with dapagliflozin was predicted to reduce rates of CKD progression, with patients predicted to spend 1.7 (95% credibility interval, 0.8 to 2.4) more years in the eGFR range 15-89 ml/min per 1.73 m2 versus standard therapy alone (12.1; 95% credibility interval, 8.9 to 14.1 versus 10.4; 95% credibility interval, 7.7 to 12.4 years). Life expectancy (undiscounted) was correspondingly predicted to increase by 1.7 (95% credibility interval, 0.7 to 2.5) years (15.5; 95% credibility interval, 11.1 to 18.2 versus 13.8; 95% credibility interval, 9.9 to 16.5 years). This in addition to reduced incidence of adverse clinical outcomes, including hospitalization for heart failure, resulted in modeled quality-adjusted life year (discounted) gains between 0.82 (95% credibility interval, 0.38 to 1.18) and 1.00 (95% credibility interval, 0.46 to 1.41). These gains translated to incremental cost-effectiveness ratios of $8280, $17,623, and $11,687 in the United Kingdom, Germany, and Spain, respectively, indicating cost-effectiveness at willingness-to-pay thresholds (United Kingdom: $27,510 per quality-adjusted life year; Germany and Spain: $35,503 per quality-adjusted life year). CONCLUSIONS: In patients meeting the eligibility requirements for the DAPA-CKD trial, dapagliflozin is likely to be a cost-effective treatment within the UK, German, and Spanish health care systems. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Dapagliflozin and Prevention of Adverse Outcomes in CKD (DAPA-CKD), NCT03036150.

Healing the past, reimagining the present, investing in the future: What should be the role of race as a proxy covariate in health economics informed health care policy?

In this perspective, the assertion that race-free risk assessment would harm patients of all races is critiqued from the viewpoint that race is not just another covariate in our arsenal. Although race may be associated with outcome, it is nevertheless a proxy for a myriad of other potential explanatory variables that could be genetic/biological but in many circumstances are more likely to be sociological/socioeconomic. It is argued that the pursuit of health maximization through the use of socially constructed variables like race must be done sensitively, recognizing that racial covariates in the medical arena can be subject to structural, institutional or personal biases. Even when such biases are thought to be minimized, the appearance of such bias may be sufficient to justify the removal of its use, particularly where employing a racial covariate could further increase existing disparities. While racial covariates may have descriptive value in helping to understand such disparities, it is beholden on the scientific community to explore alternatives to racial covariates that may provide the same or perhaps even better prognostic value in our analyses.

How can we optimise health technology assessment and reimbursement decisions to accelerate access to new cardiovascular medicines?

Regulatory approvals of, and subsequent access to, innovative cardiovascular medications have declined. How much of this decline relates to the final step of gaining reimbursement for new treatments is unknown. Payers and health technology assessment (HTA) bodies look beyond efficacy and safety to assess whether a new drug improves patient outcomes, quality of life, or satisfaction at a cost that is affordable compared to existing treatments. HTA bodies work within a limited healthcare budget, and this is one of the reasons why only half of newly approved drugs are accepted for reimbursement, or receive restricted or "optimised" recommendations from HTA bodies. All stakeholders have the common goal of facilitating access to safe, effective, and affordable treatments to appropriate patients. An important strategy to expedite this is providing optimal data. This is demonstrably facilitated by early (and ongoing) discussions between all stakeholders. Many countries have formal programmes to provide collaborative regulatory and HTA advice to developers. Other strategies include aligning regulatory and HTA processes, increasing use of real-world evidence, formally defining the decision-making process, and educating stakeholders on the criteria for positive decision making. Industry should focus on developing treatments for unmet medical needs, seek early engagement with HTA and regulatory bodies, improve methodologies for optimal price setting, develop internal systems to collaborate with national and international stakeholders, and conduct post-approval studies. Patient involvement in all stages of development, including HTA, is critical to capture the lived experience and priorities of those whose lives will be impacted by new treatment approvals.

Cost-Effectiveness Analysis of Molnupiravir Versus Best Supportive Care for the Treatment of Outpatient COVID-19 in Adults in the US.

BACKGROUND AND AIMS: Coronavirus disease 2019 (COVID-19) imposes a substantial and ongoing burden on the US healthcare system and society. Molnupiravir is a new oral antiviral for treating COVID-19 in outpatient settings. This study evaluated the cost-effectiveness profile of molnupiravir versus best supportive care in the treatment of adult patients with mild-to-moderate COVID-19 at risk of progression to severe disease, from a US payer's perspective. METHODS: The model was developed using a decision tree for the short-term acute phase of COVID-19 and a Markov state transition model for the long-term post-acute phase. This model compared molnupiravir with best supportive care as consistent with the MOVe-OUT trial. Costs were reported in 2021 US dollars. Transition probabilities were derived from the phase III MOVe-OUT trial and the TriNetX real-world electronic health records database. Costs were derived from the TriNetX database and utility values from a de novo, vignette-based utility study. Deterministic and probabilistic sensitivity analyses (DSA/PSA) were conducted. Primary outcomes included proportion hospitalized, proportion who died overall and by highest healthcare setting at the end of the acute phase, quality-adjusted life-years (QALYs), and incremental costs per QALY gained over a lifetime (100 years) horizon, discounted at 3% annually and assessed at a willingness-to-pay (WTP) threshold of $100,000 per QALY. RESULTS: In this model, the use of molnupiravir led to an increase in QALYs (0.210) and decrease in direct total medical costs (-$895) per patient across a lifetime horizon, compared with best supportive care in COVID-19 outpatients. Molnupiravir was the dominant intervention when compared with best supportive care. Patients treated with molnupiravir were less likely to be hospitalized (6.38% vs. 9.20%) and more likely to remain alive (99.88% vs. 98.71%) during the acute phase. Through DSA, molnupiravir treatment effect of hospitalization reduction was identified to be the most influential parameter, and through PSA, molnupiravir remained dominant in 84% of the total simulations and, overall, 100% cost effective. CONCLUSION: This analysis suggests that molnupiravir is cost effective compared with best supportive care for the treatment of adult outpatients with COVID-19. However, our study was limited by the unavailability of the most recent information on the rapidly evolving pandemic, including new viral variants, patient populations affected, and changes in standards of care. Further research should explore the impact of vaccination on the cost effectiveness of molnupiravir and other therapies, based on real-world data, to account for these changes, including the impact of vaccination and immunity.

Fracture liaison service utilising an emergency department information system to identify patients effectively reduce re-fracture rate is cost-effective and cost saving in Western Australia.

OBJECTIVES: To assess the benefits of the Emergency Department Information System (EDIS)-linked fracture liaison service (FLS). METHODS: Patients identified through EDIS were invited to attend an FLS at the intervention hospital, the Sir Charles Gairdner Hospital (SCGS-FLS). The intervention group was compared to usual care. Retrospective control (RC) at this hospital determined historical fracture risk (SCGH-RC). Prospective control (PC) was from a comparator, Fremantle Hospital (FH-PC). The main outcome measures were cost-effectiveness from a health system perspective and quality of life by EuroQOL (EQ-5D). Bottom-up cost of medical care, against the cost of managing recurrent fracture (weighted basket), was determined from the literature and 2013/14 Australian Refined Diagnosis Related Groups (AR-DRG) prices. Mean incremental cost-effectiveness ratios were simulated from 5000 bootstrap iterations. Cost-effectiveness acceptability curves were generated. RESULTS: The SCGH-FLS program reduced absolute re-fracture rates versus control cohorts (9.2-10.2%), producing an estimated cost saving of AUD$750,168-AUD$810,400 per 1000 patient-years in the first year. Between-groups QALYs differed with worse outcomes in both control groups (p < 0.001). The SCGH-FLS compared with SCGH-RC and FH-PC had a mean incremental cost of $8721 (95% CI -$1218, $35,044) and $8974 (95% CI -$26,701, $69,929), respectively, per 1% reduction in 12-month recurrent fracture risk. The SCGH-FLS compared with SCGH-RC and FH-PC had a mean incremental cost of $292 (95% CI -$3588, $3380) and -$261 (95% CI -$1521, $471) per EQ-5D QALY gained at 12 months respectively. With societal willingness to pay of $16,000, recurrent fracture is reduced by 1% in >80% of patients. CONCLUSIONS: This simple and easy model of identification and intervention demonstrated efficacy in reducing rates of recurrent fracture and was cost-effective and potentially cost saving.

Comparison of Alternative Methods to Assess the Cost-Effectiveness of Tumor-Agnostic Therapies: A Triangulation Approach Using Larotrectinib as a Case Study.

OBJECTIVES: The study objective was to investigate the economic value of tumor-agnostic therapies when only single-arm effectiveness data are available at launch by applying multiple methodologies to establish comparative effectiveness. METHODS: In the absence of direct comparative data, 3 methods were used to estimate the counterfactual: (1) a historical control based on a systematic literature review for each tumor site from the larotrectinib trials, (2) an intracohort comparison using the previous line of therapy time to progression from larotrectinib trials, and (3) a nonresponder control that applied outcomes for larotrectinib nonresponders. Cost-effectiveness was modeled using the partitioned survival approach. Stochastic parameter uncertainty was assessed in a probabilistic sensitivity analysis (PSA). A triangulated estimate of the mean cost-effectiveness result was generated combining all 3 counterfactual estimates. RESULTS: Incremental cost-effectiveness ratios were similar across the 3 methodologies in the deterministic analysis ranging from £83 868 (95% uncertainty interval [UI] £65 698-£107 668) to £104 922 per quality-adjusted life-year (95% UI £80 132-£139 658). PSA results for each method substantially overlapped when plotted on the cost-effectiveness plane. Weighting PSA results for each method equally in the triangulation method produced an incremental cost-effectiveness ratios of £95 587 per quality-adjusted life-year gained (95% UI £70 449-£137 431). CONCLUSIONS: In the absence of direct comparative data, different methods of estimating a counterfactual are possible, each with strengths and limitations. Triangulating results across the methods provides a composite view of the total uncertainty and a more consistent estimation of the cost-effectiveness of the tumor-agnostic intervention compared with choosing a single method.