Application of Multi-Criteria Decision Analysis (MCDA) to Prioritize Real-World Evidence Studies for Health Technology Management: Outcomes and Lessons Learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration.

Multi-criteria decision analysis (MCDA) is a value assessment tool designed to help support complex decision-making by incorporating multiple factors and perspectives in a transparent, structured approach. We developed an MCDA rating tool, consisting of seven criteria evaluating the importance and feasibility of conducting potential real-world evidence (RWE) studies aimed at addressing uncertainties stemming from initial cancer drug funding recommendations. In collaboration with the Canadian Agency for Drugs and Technologies in Health's Provincial Advisory Group, a validation exercise was conducted to further evaluate the application of the rating tool using RWE proposals varying in complexity. Through this exercise, we aimed to gain insight into consensus building and deliberation processes and to identify efficiencies in the application of the rating tool. An experienced facilitator led a multidisciplinary committee, consisting of 11 Canadian experts, through consensus building, deliberation, and prioritization. A total of nine RWE proposals were evaluated and prioritized as low (n = 4), medium (n = 3), or high (n = 2) priority. Through an iterative process, efficiencies and recommendations to improve the rating tool and associated procedures were identified. The refined MCDA rating tool can help decision-makers prioritize important and feasible RWE studies for research and can enable the use of RWE for the life-cycle evaluation of cancer drugs.

Development of a Multi-Criteria Decision Analysis Rating Tool to Prioritize Real-World Evidence Questions for the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration.

The Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration developed an MCDA rating tool to assess and prioritize potential post-market real-world evidence (RWE) questions/uncertainties emerging from public drug funding decisions in Canada. In collaboration with a group of multidisciplinary stakeholders from across Canada, the rating tool was developed following a three-step process: (1) selection of criteria to assess the importance and feasibility of an RWE question; (2) development of rating scales, application of weights and calculating aggregate scores; and (3) validation testing. An initial MCDA rating tool was developed, composed of seven criteria, divided into two groups. Group A criteria assess the importance of an RWE question by examining the (1) drug's perceived clinical benefit, (2) magnitude of uncertainty identified, and (3) relevance of the uncertainty to decision-makers. Group B criteria assess the feasibility of conducting an RWE analysis including the (1) feasibility of identifying a comparator, (2) ability to identify cases, (3) availability of comprehensive data, and (4) availability of necessary expertise and methodology. Future directions include partnering with the Canadian Agency for Drugs and Technology in Health's Provincial Advisory Group for further tool refinement and to gain insight into incorporating the tool into drug funding deliberations.

Real-World Cost-Effectiveness of First-Line Gemcitabine Plus Nab-Paclitaxel vs FOLFIRINOX in Patients With Advanced Pancreatic Cancer.

BACKGROUND: There are no randomized control trials (RCTs) comparing gemcitabine and nab-paclitaxel (Gem-Nab) and fluorouracil, folinic acid, irinotecan, oxaliplatin (FOLFIRINOX) for advanced pancreatic cancer (APC). Although it is well known that RCT-based efficacy often does not translate to real-world effectiveness, there is limited literature investigating comparative cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC. We aimed to examine the real-world cost-effectiveness of Gem-Nab vs FOLFIRINOX for APC in Ontario, Canada. METHODS: This study compared patients treated with first-line Gem-Nab or FOLFIRINOX for APC in Ontario from April 2015 to March 2019. Patients were linked to administrative databases. Using propensity scores and a stabilizing weights method, an inverse probability of treatment weighted cohort was developed. Mean survival and total costs were calculated over a 5-year time horizon, adjusted for censoring, and discounted at 1.5%. Incremental cost-effectiveness ratio and net monetary benefit were computed to estimate cost-effectiveness from the public health-care payer's perspective. Sensitivity analysis was conducted using the propensity score matching method. RESULTS: A total of 1988 patients were identified (Gem-Nab: n = 928; FOLFIRINOX: n = 1060). Mean survival was lower for patients in the Gem-Nab than the FOLFIRINOX group (0.98 vs 1.26 life-years; incremental effectiveness = -0.28 life-years [95% confidence interval = -0.47 to -0.13]). Patients in the Gem-Nab group incurred greater mean 5-year total costs (Gem-Nab: $103 884; FOLFIRINOX: $101 518). Key cost contributors include ambulatory cancer care, acute inpatient hospitalization, and systemic therapy drug acquisition. Gem-Nab was dominated by FOLFIRINOX, as it was less effective and more costly. Results from the sensitivity analysis were similar. CONCLUSIONS: Gem-Nab is likely more costly and less effective than FOLFIRINOX and therefore not considered cost-effective at commonly accepted willingness-to-pay thresholds.

Parametric Survival Extrapolation of Early Survival Data in Economic Analyses: A Comparison of Projected Versus Observed Updated Survival.

OBJECTIVES: To establish the value of cancer drugs by cost-effectiveness analysis, lifetime parametric survival extrapolations are often fitted to early data. Recent literature suggests that the benefit of cancer agents in primary publications is often different compared with updated data. This study aimed to examine the projected survival based on parametric extrapolations compared with observed survival based on updated data. METHODS: US Food and Drug Administration oncology approvals from January 2006 to December 2015 were reviewed to identify randomized controlled trials, with updated overall survival (OS) or progression-free survival (PFS) data within 5 years. Individual patient data were reconstructed using established methods on initial and updated publications. Projected survival was calculated as the best-fit parametric restricted mean survival time (RMST) based on extrapolated initial Kaplan-Meier curves whereas observed survival was calculated as observed RMST based on updated Kaplan-Meier curves. Mean deviations, mean absolute error (MAE), mean absolute percentage error, and linear regressions were conducted to examine the relationship between projected and observed survival. RESULTS: In total, 32 randomized controlled trials were included. The MAE between the projected RMST and observed RMST was 3.18 months (OS) and 2.84 months (PFS) and absolute percentage error of 100% (OS) and 23% (PFS), suggesting substantial imprecision of the projected RMST in predicting the updated RMST. The linear regression indicated MAE increased as time extrapolated and as the percentage of censored patients increased. CONCLUSIONS: This study demonstrated substantial difference in projected survival between initial and updated publications. Health technology assessment committees need to be aware of the potential uncertainty of incremental effectiveness and resultant value-for-money assessment when making reimbursement decisions based on initial publications with immature survival data.

Cancer treatment-related financial toxicity experienced by patients in low- and middle-income countries: a scoping review.

PURPOSE: In the past decade, literature has called attention to financial toxicities experienced by cancer patients. Though studies have addressed research questions in high-income countries, there remains a paucity of in-depth reviews regarding low- and middle-income countries (LMICs). Our scoping review provides an overview of treatment-related financial toxicities experienced by cancer patients in LMICs. METHODS: A systematic search was conducted in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. English peer-reviewed articles that (a) explored patients' experience with financial toxicity due to cancer treatment (b) were specific to LMICs as defined by the World Bank and (c) focused on qualitative data were included. Details regarding participants and main findings were extracted and synthesized. RESULTS: The search yielded 6290 citations, and 42 studies across 3 low-income, 9 lower-middle-income and 8 upper-middle-income countries. Main themes identified included cancer patients encountered various material hardships, managed costs with different coping behaviours and experienced negative psychological responses to their financial burden. Higher levels of financial toxicities were associated with patient characteristics such as lower socio-economic status and lack of insurance, as well as patient outcomes such as lower quality of life. CONCLUSION: Cancer patients in LMIC experience deleterious financial toxicities as a result of treatment. This comprehensive characterization of financial toxicities will better allow health systems to adopt evidence-based mitigation strategies to reduce the financial burden on patients.

A cost-utility analysis of apalutamide for metastatic castrationsensitive prostate cancer.

INTRODUCTION: Earlier application of oral androgen receptor-axis-targeted therapies in patients with metastatic castration-sensitive prostate cancer (mCSPC) has established improvements in overall survival, as compared to androgen deprivation therapy (ADT) alone. Recently, the use of apalutamide plus ADT has demonstrated improvement in mCSPC-related mortality vs. ADT alone, with an acceptable toxicity profile. However, the cost-effectiveness of this therapeutic option remains unknown. METHODS: We used a state-transition model with probabilistic analysis to compare apalutamide plus ADT, as compared to ADT alone, for mCSPC patients over a time horizon of 20 years. Primary outcomes included expected life-years (LY), quality-adjusted life-years (QALY), lifetime cost (2020 Canadian dollars), and incremental cost-effectiveness ratio (ICER). Parameter and model uncertainties were assessed through scenario analyses. Health outcomes and cost were discounted at 1.5%, as per Canadian guidelines. RESULTS: For the base-case analysis, expected LY for ADT and apalutamide plus ADT were 4.11 and 5.56, respectively (incremental LY 1.45). Expected QALYs were 3.51 for ADT and 4.84 for apalutamide plus ADT (incremental QALYs 1.33); expected lifetime cost was $36 582 and $255 633, respectively (incremental cost $219 051). ICER for apalutamide plus ADT, as compared to ADT alone, was $164 700/QALY. Through scenario analysis, price reductions ≥50% were required for apalutamide in combination with ADT to be considered cost-effective, at a cost-effectiveness threshold of $100 000/QALY. CONCLUSIONS: Apalutamide plus ADT is unlikely to be cost-effective from the Canadian healthcare perspective unless there are substantial reductions in the price of apalutamide treatment.

Building a National Reassessment Process for Oncology Drugs: Lessons Learned by the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration through a Simulated Reassessment Exercise.

The CanREValue Collaboration established the Reassessment & Uptake Working Group to develop a preliminary process to reassess funded cancer drugs in Canada. A simulated exercise was conducted to evaluate the proposed reassessment process using a real-world case. We invited 32 attendees including representatives from Health Canada and Health Technology Assessment (HTA) agencies, along with payers, clinicians, academics, and patient representatives. A case was developed using a real-world study on a publicly funded cancer drug. In facilitated group sessions, participants were asked to deliberate upon the evidence presented in the case to issue reassessment recommendations. Several themes were identified through the deliberation discussions. While the generalizability of real-world evidence (RWE) is perceived as a strength, trust in the RWE depends largely on the source of the real-world data. The attendees suggested several improvements to the proposed reassessment process including evidence requirement for reassessment, recommendation categories, and a priori study protocols. This exercise generated important insights on the evidence required for conducting reassessment and considerations for improvements of the proposed reassessment process. Building upon lessons from this exercise, future work would continue to refine the reassessment process as part of the overall CanREValue framework.

The Edmonton Symptom Assessment System: A narrative review of a standardized symptom assessment tool in head and neck oncology.

OBJECTIVE: Symptom burden is common in head and neck cancer patients though it frequently remains undetected and untreated. The Edmonton Symptom Assessment System - revised version (ESAS-r) is a generic symptom scale deployed in many outpatient settings worldwide. The ESAS-r is meant to improve symptom detection and management. We sought to review the ESAS-r and its psychometric properties in a head and neck oncology population. METHODS: Narrative Review. RESULTS: Over the past 30 years, the ESAS-r has emerged as one of the most used symptom scales for cancer patients. Its psychometric properties in a heterogenous cancer population are well supported, proving to be reliable and valid in a variety of settings. The linking of ESAS-r scores with Ontario administrative health data has led to a detailed assessment of validity in head and neck cancer. The ESAS-r can discriminate between high and low levels of symptom burden and is responsive to change over time in this patient population. ESAS-r scores have also been shown to be a strong predictor of future emergency department use and unplanned hospitalization in head and neck cancer patients. CONCLUSIONS: The ESAS-r is reliable and valid in the head and neck cancer population and may serve as a useful clinical endpoint in research studies.

Considerations for Developing a Reassessment Process: Report from the Canadian Real-World Evidence for Value of Cancer Drugs (CanREValue) Collaboration's Reassessment and Uptake Working Group.

The Canadian Real-world Evidence for Value in Cancer Drugs (CanREValue) Collaboration was established to develop a framework for generating and using real-world evidence (RWE) to inform the reassessment of cancer drugs following initial health technology assessment (HTA). The Reassessment and Uptake Working Group (RWG) is one of the five established CanREValue Working Groups. The RWG aims to develop considerations for incorporating RWE for HTA reassessment and strategies for using RWE to reassess drug funding decisions. Between February 2018 and December 2019, the RWG attended four teleconferences (with follow-up surveys) and two in-person meetings to discuss recommendations for the development of a reassessment process and potential barriers and facilitators. Modified Delphi methods were used to gather input. A draft report of recommendations (to December 2018) was shared for public consultation (December 2019 to January 2020). Initial considerations for developing a reassessment process were proposed. Specifically, reassessment can be initiated by diverse stakeholders, including decision makers from public drug plans or industry stakeholders. The reassessment process should be modelled after existing deliberation and recommendation frameworks used by HTA agencies. Proposed reassessment outcome categories include maintaining status quo, revisiting funding criteria, renegotiating price, or disinvesting. Overall, these initial considerations will serve as the basis for future advancements by the Collaboration.

Assessment of Food and Drug Administration- and European Medicines Agency-Approved Systemic Oncology Therapies and Clinically Meaningful Improvements in Quality of Life: A Systematic Review.

Importance: For patients with cancer treated with palliative intent, quality of life (QOL) is a critical aspect of treatment decision-making, alongside survival. However, regulatory approval can be based solely on survival measures or antitumor activities, without QOL evidence. Objective: To investigate whether recently approved oncology therapies demonstrate clinically meaningful improvements in QOL. Evidence Review: This systematic review study identified oncology drug indications approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) from January 2006 to December 2017 and supporting clinical trials (QOL publications identified to October 2019). Indications were evaluated for the presence of published QOL evidence; QOL benefits according to the American Society of Clinical Oncology Value Framework version 2.0 (ASCO-VF) and European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS) QOL bonus criteria; and clinically meaningful improvements in QOL beyond minimal clinically important differences. Hematology trials were not evaluated by ESMO-MCBS. Associations between QOL evidence and approval year were examined using logistic regression models. Findings: In total, 214 FDA-approved (77 [36%] hematological) and 170 EMA-approved (52 [31%] hematological) indications were included. QOL evidence was published for 40% and 58% of FDA- and EMA-approved indications, respectively. QOL bonus criterion for ASCO-VF and ESMO-MCBS was met in 13% and 17% of FDA-approved and 21% and 24% of EMA-approved indications, respectively. Clinically meaningful improvements in QOL beyond minimal clinically important differences were noted in 6% and 11% of FDA- and EMA-approved indications, respectively. Availability of published QOL evidence at the time of approval increased over time for EMA (odds ratio [OR], 1.13; P = .03), however not for FDA (OR, 1.10; P = .12). Over time, no increase in awarded QOL bonuses or clinically meaningful improvements in QOL were found. Conclusions and Relevance: The findings of this systematic review suggest that approved systemic oncology therapies often do not have published evidence to suggest QOL improvement, despite its recognized importance. Of indications with evidence of statistical improvement, few have demonstrated clinically meaningful improvements.

Nonsurgical management of resectable oral cavity cancer in the wake of COVID-19: A rapid review and meta-analysis.

OBJECTIVE: Surgery is the preferred treatment modality for oral squamous cell carcinoma (OSCC). However, due to limited resources, re-assessment of treatment paradigms in the wake of the Coronavirus Disease 2019 (COVID-19) pandemic is urgently required. In this rapid review, we described contemporary oncological outcomes for OSCC using non-surgical modalities. METHODS: A systematic literature search was conducted for articles published between January 1, 2010 and April 1, 2020 on MEDLINE and Cochrane CENTRAL. Studies were included if they contained patients with OSCC treated with either neoadjuvant, induction, or definitive radiotherapy, chemotherapy, immunotherapy, or combination thereof, and an outcome of overall survival. RESULTS: In total, 36 articles were included. Definitive radiotherapy or chemoradiotherapy were the focus of 18 articles and neoadjuvant chemotherapy or chemoradiotherapy were the focus of the other 18 articles. In early stage OSCC, definitive radiotherapy, with or without concurrent chemotherapy, was associated with a significantly increased hazard of death compared to definitive surgery (HR: 2.39, 95% CI: 1.56-3.67, I2: 63%). The hazard of death was non-significantly increased with definitive chemoradiotherapy in studies excluding early disease (HR: 1.98, 95% CI: 0.85-4.64, I2: 84%). Two recent randomized control trials have been conducted, demonstrating no survival advantage to neoadjuvant chemotherapy. CONCLUSION: This review suggests that primary radiotherapy and chemoradiotherapy are inferior to surgical management for OSCC. Strategies for surgical delay warranting consideration are sparse, but may include several neoadjuvant regimens, recognizing these regimens may not offer a survival benefit over definitive surgery alone.

Socioeconomic disparity trends in diagnostic imaging, treatments, and survival for non-small cell lung cancer 2007-2016.

Socioeconomic status (SES) has led to treatment and survival disparities; however, limited data exist for non-small cell lung cancer (NSCLC). This study investigates the impact of SES on NSCLC diagnostic imaging, treatment, and overall survival (OS), and describes temporal disparity trends. The Ontario Cancer Registry was used to identify NSCLC patients diagnosed between 2007 and 2016. Through linkage to administrative datasets, patients' demographics, imaging, treatment, and survival were obtained. Based on median household neighborhood income, the Ontario population was divided into five income quintiles (Q1-Q5; Q1 = lowest income). Multivariable regressions assessed SES association with OS, imaging, treatment receipt, and treatment delay, and their interaction with year of diagnosis to understand temporal trends. Endpoints were adjusted for demographics, stage and comorbidities, along with treatments and imaging for OS. A total of 50 542 patients were identified. Higher SES patients (Q5 vs. Q1) showed improved 5-year OS (hazard ratio, 0.89; 95% confidence interval [CI], 0.87-0.92; P < .0001) and underwent greater magnetic resonance imaging head (stages IA-IV; odds ratio [OR], 1.24; 95% CI, 1.16-1.32; P < .0001), lung resection (IA-IIIA; OR, 1.58; 95% CI, 1.43-1.74; P < .0001), platinum-based vinorelbine adjuvant chemotherapy (IB-IIIA; OR, 1.63; 95% CI, 1.39-1.92; P < .0001), palliative radiation (IV; OR, 1.14; 95% CI, 1.05-1.25; P = .023), and intravenous chemotherapy (IV; OR, 1.45; 95% CI, 1.32-1.60; P < .0001). Lower SES patients underwent greater thoracic radiation (IA-IIIB; OR, 0.86; 95% CI, 0.79-0.94; P = .0003). Across 2007-2016, socioeconomic disparities remain largely unchanged (interaction P > .05) despite widening income inequality.

Value-based pricing: Toward achieving a balance between individual and population gains in health benefits.

OBJECTIVES: Value-based pricing of oncology drugs provides a best estimate for the price of a drug, as it relates to the benefits it provides for individual patients. To date, the impact of value-based pricing to reference cost-effectiveness thresholds (λ) on individual and population-level health benefits remains uncharacterized. The current study examined the potential benefits of value-based pricing by quantifying the incremental net health benefit (INHB) of publicly funded oncology drugs, if funding occurred at manufacturer-submitted price without value-based pricing. METHODS: Pan-Canadian Oncology Drug Review (pCODR) submissions were reviewed to identify eligible drug indications from which final economic guidance panel reports were reviewed for incremental costs (ΔC) and quality-adjusted life-years (ΔQALY) from manufacturer-submitted, pCODR lower-limit (pCODR-LL) and upper-limit (pCODR-UL) re-analyzed estimates. Annual number of cases in Ontario for each drug indication was obtained from population databases. Annual QALY gain per drug indication was determined by (ΔQALY × cases). Population QALY gain/loss in the absence of value-based pricing to reference λ was estimated by the INHB: (INHB = [ΔQALY - (ΔC/λ)] × cases). RESULTS: In total, 34 drug indications (4629 cases) were identified. Annual gain in QALYs for the funded drug indications using manufacturer, pCODR-LL, and pCODR-UL estimates was 1851, 1617, and 1301, respectively. At a λ $100 000/QALY, funding in the absence of value-based pricing resulted in loss of 2311, 2519, and 2604 QALYs. This would result in a provincial net annual loss of 460, 902, and 1303 QALYs. CONCLUSIONS: Despite an annual gain in QALY per funded drug indication, a net loss in QALY for the province, in the absence of value-based pricing, was demonstrated. Supportive evidence exists for value-based pricing toward the promotion of health benefits for the greater population.