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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.

Introduction For patients with diffuse large B‐cell lymphoma (DLBCL), standard‐care is rituximab administered with CHOP or CHOP‐like chemotherapy (R‐CHOP). However, the effectiveness and safety of R‐CHOP among DLBCL patients with human immunodeficiency virus (HIV) infection is less clear, as HIV+ patients were omitted from most clinical trials and population‐level data from unselected patients are limited. R‐CHOP was funded for HIV‐associated DLBCL patients with CD4 >50/mm3 in Ontario in February 2015. Methods Patients with a new diagnosis of DLBCL were identified from the Ontario Cancer Registry between April 2010 and March 2018. HIV diagnosis and chemotherapy regimen were ascertained using administrative databases at Ontario Health. The effect of rituximab and HIV on overall survival was assessed in the HIV+ subgroup (R‐CHOP vs CHOP) and in the R‐CHOP subgroup (HIV+ vs HIV−). Results Among HIV+ patients, receipt of R‐CHOP was associated with a fivefold improvement in overall survival (hazard ratio [HR] 0.29 (0.13‐0.66) compared with CHOP), after adjustment. Among patients who received R‐CHOP (n = 6106), older age, male sex, lower neighborhood income, and higher comorbidity were associated with worse overall survival, after adjustment (P, The standard of care for patients with aggressive‐histology B‐cell lymphoma is rituximab in addition to a CHOP or CHOP‐like chemotherapy regimen. For HIV+ patients, there are less data available on the effectiveness of this treatment, but in 2015, policy changes in Ontario extended this treatment modality to this subgroup of patients. In the present study, we demonstrate that rituximab with CHOP is as safe and effective for HIV+ patients as it is for HIV− patients.

Introduction While no direct comparative data exist for crizotinib in ROS1+ non-small cell lung cancer (NSCLC), studies have suggested clinical benefit with this targeted agent. The objective of this study was to assess the cost-effectiveness of crizotinib compared to standard platinum-doublet chemotherapy for first-line treatment of ROS1+ advanced NSCLC. Methods A Markov model was developed with a 10-year time horizon from the perspective of the Canadian publicly-funded health care system. Health states included progression-free survival (PFS), up to two further lines of therapy post-progression, palliation and death. Given a lack of comparative data and small study samples, crizotinib or chemotherapy studies with advanced ROS1+ NSCLC patients were identified and time-to-event data from digitized Kaplan-Meier curves were collected to pool PFS data. Costs of drugs, treatment administration, monitoring, adverse events and palliative care were included in 2018 Canadian dollars, with 1.5% discounting. An incremental cost-effectiveness ratio (ICER) was estimated probabilistically using 5000 simulations. Results In the base-case probabilistic analysis, crizotinib produced additional 0.885 life-years and 0.772 quality-adjusted life-years (QALYs) at an incremental cost of $238,077, producing an ICER of $273,286/QALY gained. No simulations were found to be cost-effective at a willingness-to-pay threshold of $100,000/QALY gained. A scenario analysis assuming efficacy equivalent to the ALK+ NSCLC population showed a slightly more favorable cost-effectiveness profile for crizotinib. Conclusions Available data appear to support superior activity of crizotinib compared to chemotherapy in ROS1+ advanced NSCLC. At the list price, crizotinib was not cost-effective at commonly accepted willingness-to-pay thresholds across a wide range of sensitivity analyses.

Background Advanced pancreatic cancer (APC) patients often have substantial symptom burden. In Ontario, patients routinely complete the Edmonton Symptom Assessment Scale (ESAS), which screens for nine symptoms (scale: 0‐10), in cancer clinics. We explored the association between baseline patient‐reported outcomes, via ESAS, and overall survival (OS). Methods Advanced pancreatic cancer patients with ESAS records prior to receiving publicly funded drugs from November 2008 to March 2016 were retrospectively identified from Cancer Care Ontario's administrative databases. We examined three composite ESAS scores: total symptom distress score (TSDS: 9 symptoms), physical symptom score (PHS: 6/9 symptoms), and psychological symptom score (PSS: 2/9 symptoms); Composite scores greater than defined thresholds (TSDS ≥36, PHS ≥24, PSS ≥8) were considered as high symptom burden. Crude OS was assessed using Kaplan‐Meier method. Hazard ratios (HRs) were assessed using multivariable Cox models. Analysis was repeated in a sub‐cohort with Eastern Cooperative Oncology Group (ECOG) status and metastasis. Results We identified 2199 APC patients (mean age 64 years, 55% male) with ESAS records prior to receiving chemotherapy. Crude median survival was 4.5 and 7.3 months for high and low TSDS, respectively. High TSDS was associated with lower OS (HR = 1.47, 95% CI: 1.33, 1.63). In the sub‐cohort (n = 393) with ECOG status and metastasis, high TSDS was also associated with lower OS (HR = 1.34, 95% CI: 1.04, 1.73). Similar trends were observed for PHS and PSS. Conclusions Higher burden of patient‐reported outcome was associated with reduced OS among APC patients. The effect was prominent after adjusting for ECOG status., In a cohort of advanced pancreatic cancer patients, we observed that higher burden of patient‐reported symptoms at baseline is associated with reduced overall survival. The association remained significant after accounting for performance status and type of treatment.

Background. Real-world evidence can be a valuable tool when clinical trial data are incomplete or uncertain. Bevacizumab was adopted as first-line therapy for metastatic colorectal cancer (mCRC) based on significant survival improvements in initial clinical trials; however, survival benefit diminished in subsequent analyses. Consequently, there is uncertainty surrounding the cost-effectiveness of bevacizumab therapy achieved in practice. Objective. To assess real-world cost-effectiveness of first-line bevacizumab with irinotecan-based chemotherapy versus irinotecan-based chemotherapy alone for mCRC in British Columbia (BC), Saskatchewan, and Ontario, Canada. Methods. Using provincial cancer registries and linked administrative databases, we identified mCRC patients who initiated publicly funded irinotecan-based chemotherapy, with or without bevacizumab, in 2000 to 2015. We compared bevacizumab-treated patients to historical controls (treated before bevacizumab funding) and contemporaneous controls (receiving chemotherapy without bevacizumab), using inverse-probability-of-treatment weighting with propensity scores to balance baseline covariates. We calculated incremental cost-effectiveness ratios (ICER) using 5-year cost and survival adjusted for censoring, with bootstrapping to characterize uncertainty. We also conducted one-way sensitivity analysis for key drivers of cost-effectiveness. Results. The cohorts included 12,112 (Ontario), 1,161 (Saskatchewan), and 2,977 (BC) patients. Bevacizumab significantly increased treatment costs, with mean ICERs between $78,000 and $84,000/LYG (life-year gained) in the contemporaneous comparisons and $75,000 and $101,000/LYG in the historical comparisons. Reducing the cost of bevacizumab by 50% brought ICERs in all comparisons below $61,000/LYG. Limitations. Residual confounding in observational data may bias results, while the use of original list prices overestimates current bevacizumab cost. Conclusion. The addition of bevacizumab to irinotecan-based chemotherapy extended survival for mCRC patients but at significant cost. At original list prices bevacizumab can only be considered cost-effective with certainty at a willingness-to-pay threshold over $100,000/LYG, but price reductions or discounts have a significant impact on cost-effectiveness.

Background For novel cancer treatments, effectiveness in clinical practice is not always aligned with clinical efficacy results. As such it is important to understand a treatment’s real-world effectiveness. We examined real-world population-based comparative effectiveness of second-line ipilimumab versus non-ipilimumab treatments (chemotherapy or targeted treatments). Methods We used a cohort of melanoma patients receiving systemic treatment for advanced disease since April 2005 from Ontario, Canada. Patients were identified from provincial drug databases and the Ontario Cancer Registry who received second-line ipilimumab from 2012 to 2015 (treated) or second-line non-ipilimumab treatment prior to 2012 (historical controls). Historical controls were chosen, to permit the most direct comparison to pivotal trial findings. The cohort was linked to administrative databases to identify baseline characteristics and outcomes. Kaplan-Meier curves and multivariable Cox regression models were used to assess overall survival (OS). Observed potential confounders were adjusted for using inverse probability of treatment weighting (IPTW). Results We identified 329 patients with metastatic melanoma (MM) who had received second-line treatments (189 treated; 140 controls). Patients receiving second-line ipilimumab were older (61.7 years vs 55.2 years) compared to historical controls. Median OS were 6.9 (95% CI: 5.4–8.3) and 4.95 (4.3–6.0) months for ipilimumab and controls, respectively. The crude 1-year, 2-year, and 3-year OS probabilities were 34.3% (27–41%), 20.6% (15–27%), and 15.2% (9.6–21%) for ipilimumab and 17.1% (11–23%), 7.1% (2.9–11%), and 4.7% (1.2–8.2%) for controls. Ipilimumab was associated with improved OS (IPTW HR = 0.62; 95% CI: 0.49–0.78; p Conclusions This real-world analysis suggests second-line ipilimumab is associated with an improvement in OS for MM patients in routine practice.

Key Points Question Are drug-funding reimbursement decisions associated with uptake of new therapies and survival outcomes for patients with advanced pancreatic cancer? Findings In this population-based cohort study of 5465 patients with advanced pancreatic cancer receiving first-line chemotherapy within a universal health care system, reimbursement decisions were associated with uptake of new treatment options over time. Uptake of both FOLFIRINOX and gemcitabine combined with nab-paclitaxel were associated with improvements in survival for patients with pancreatic cancer. Meaning These findings suggest that drug-funding reimbursement decisions are associated with uptake of new cancer therapies and improvements in survival for patients with advanced pancreatic cancer., This cohort study investigates whether there is an association of sequential drug-funding approvals and overall survival of patients with advanced pancreatic cancer., Importance Gemcitabine-nab-paclitaxel (GEMNAB) and fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) both improve survival of patients with advanced pancreatic cancer when compared with single-agent gemcitabine in clinical trials. Objective To describe changes in the survival of patients with advanced pancreatic cancer associated with sequential drug-funding approvals and to determine if there exist distinct patient populations for whom GEMNAB and FOLFIRINOX are associated with survival benefit. Design, Setting, and Participants This population-based, retrospective cohort study examined all incident cases of advanced pancreatic cancer treated with first-line chemotherapy in Ontario, Canada (2008-2018) that were identified from the Cancer Care Ontario (Ontario Health) New Drug Funding Program database. Statistical analysis was performed from October 2020 to January 2021. Exposures First-line chemotherapy for advanced pancreatic cancer. Main Outcomes and Measures The main outcomes were the proportion of patients treated with each chemotherapy regimen over time and overall survival for each regimen. Cox proportional hazards regression models were used to compare overall survival between treatment regimens after adjustment for confounding variables, inverse probability of treatment weighting, and matching. Results From 2008 to 2018, 5465 patients with advanced pancreatic cancer were treated with first-line chemotherapy in Ontario, Canada. The median (range) age of patients was 66.9 (27.8-93.4) years; 2447 (45%) were female; 878 (16%) had prior pancreatic resection, and 328 (6%) had prior adjuvant gemcitabine. During the time period when only gemcitabine and FOLFIRINOX were funded (2011-2015), 49% (929 of 1887) received FOLFIRINOX. When GEMNAB was subsequently funded (2015-2018), 9% (206 of 2347) received gemcitabine, 44% (1034 of 2347) received FOLFIRINOX, and 47% (1107 of 2347) received GEMNAB. The median overall survival increased from 5.6 months (95% CI, 5.1-6.0 months) in 2008 to 2011 to 6.9 months (95% CI, 6.5-7.4 months) in 2011 to 2015 to 7.6 months (95% CI, 7.1-8.0 months) in 2015 to 2018. Patients receiving FOLFIRINOX were younger and healthier than patients receiving GEMNAB. After adjustment and weighting, FOLFIRINOX was associated with better overall survival than GEMNAB (hazard ratio [HR], 0.75 [95% CI, 0.69-0.81]). In analyses comparing patients treated with GEMNAB and gemcitabine, GEMNAB was associated with better overall survival (HR, 0.86 [95% CI, 0.78-0.94]). Conclusions and Relevance This cohort study of patients with advanced pancreatic cancer receiving first-line palliative chemotherapy within a universal health care system found that drug funding decisions were associated with increased uptake of new treatment options over time and improved survival. Both FOLFIRINOX and GEMNAB were associated with survival benefits in distinct patient populations.

In evaluating new oncology medicines, two common modeling approaches are state transition (e.g., Markov and semi-Markov) and partitioned survival. Partitioned survival models have become more prominent in oncology health technology assessment processes in recent years. Our experience in conducting and evaluating models for economic evaluation has highlighted many important and practical pitfalls. As there is little guidance available on best practices for those who wish to conduct them, we provide guidance in the form of 'Key steps for busy analysts,' who may have very little time and require highly favorable results. Our guidance highlights the continued need for rigorous conduct and transparent reporting of economic evaluations regardless of the modeling approach taken, and the importance of modeling that better reflects reality, which includes better approaches to considering plausibility, estimating relative treatment effects, dealing with post-progression effects, and appropriate characterization of the uncertainty from modeling itself.

BackgroundOncology therapy is becoming increasingly more expensive and challenging the affordability and sustainability of drug programmes around the world. When new drugs are evaluated, health technology assessment organisations rely on clinical trials to inform funding decisions. However, clinical trials are not able to assess overall survival and generalises evidence in a real-world setting. As a result, policy makers have little information on whether drug funding decisions based on clinical trials ultimately yield the outcomes and value for money that might be expected.ObjectiveThe Canadian Real-world Evidence for Value of Cancer Drugs (CanREValue) collaboration, consisting of researchers, recommendation-makers, decision makers, payers, patients and caregivers, are developing and testing a framework for Canadian provinces to generate and use real-world evidence (RWE) for cancer drug funding in a consistent and integrated manner.StrategyThe CanREValue collaboration has established five formal working groups (WGs) to focus on specific processes in the generation and use of RWE for cancer drug funding decisions in Canada. The different RWE WGs are: (1) Planning and Drug Selection; (2) Methods; (3) Data; (4) Reassessment and Uptake; (5) Engagement. These WGs are acting collaboratively to develop a framework for RWE evaluation, validate the framework through the multiprovince RWE projects and help to integrate the final RWE framework into the Canadian healthcare system.OutcomesThe framework will enable the reassessment of cancer drugs, refinement of funding recommendations and use of novel funding mechanisms by decision-makers/payers across Canada to ensure the healthcare system is providing clinical benefits and value for money.

In Canada, requests for public reimbursement of cancer drugs are predominately initiated by pharmaceutical manufacturers. Clinician-led submissions provide a mechanism to initiate the drug funding process when industry does not submit a request for funding consideration. Although such requests are resource-intensive to produce, Cancer Care Ontario (cco) has the capacity to facilitate clinician-led submissions. In 2014, cco began developing a cancer drug prioritization framework that allocates resources to systematically address a growing number of clinician-identified funding gaps with clinician-led submissions. Cancer site&ndash, specific drug advisory committees established by cco consist of health care practitioners whose roles include identifying and prioritizing funding gaps. The committees submit their identified gaps to a cross-cancer-site prioritization exercise in which the requests are ranked based on a set of guiding principles derived from health technology assessment. The requests are then sequentially allocated the resources needed to meet submission requirements. Whether the funding gap is of provincial or pan-Canadian relevance determines where the submission is filed for assessment. Since its inception, the cco framework has identified 17 funding gaps in 9 cancer sites. In 4 prioritizations, the framework supported 6 submissions. As of June 2018, the framework had contributed to the eventual funding of more than 9 new drug&ndash, indication pairs, with more awaiting funding consideration. The cco prioritization framework has enabled clinicians to effectively and systematically identify, prioritize, and fill funding gaps not addressed by industry. Ultimately, the framework helps to ensure that patients can access evidence-informed and cost-effective therapies. The framework will continue to evolve as it encounters new challenges, including funding requests for rare indications.

Introduction: Three pivotal trials have considered the addition of docetaxel (D) chemotherapy to conventional androgen-deprivation therapy (ADT) for the treatment of metastatic hormone-sensitive prostate cancer (HSPC). While an initial small trial was inconclusive, two larger trials demonstrated significant clinical benefit, including pronounced survival benefits (added 17 months) among patients with high-volume metastatic disease. Given the evolving clinical evidence, the cost-effectiveness of this approach warrants exploration. Methods: The cost-effectiveness of six cycles of ADT+D compared to ADT alone to treat patients with high-volume metastatic HSPC was assessed from a Canadian public payer perspective. We included three health states: HSPC, metastatic castration-resistant prostate cancer (CRPC), and death. Survival data were obtained from the CHAARTED trial, which reported outcomes specifically for high-volume disease. We used Ontario costs data and utilities from the literature. Results: In the base case analysis, ADT+D cost an additional $25 757 and produced an extra 1.06 quality-adjusted life years (QALYs), resulting in an incremental cost-effectiveness ratio (ICER) of $24 226/QALY gained. Results from one-way sensitivity analysis across wide ranges of estimates and a range of scenarios, including an alternate model structure, produced ICERs below $35 000/QALY gained in all cases. Conclusions: The use of D with ADT in high-volume metastatic HSPC appears to be an economically attractive treatment approach. The findings were consistent with other studies and robust in sensitivity analysis across a variety of scenarios.

PharmacoEconomics DOI 10.1007/s40273-015-0278-7 LETTER TO THE EDITOR Does it Matter Whether Canada’s Separate Health Technology Assessment Process for Cancer Drugs has an Economic Rationale? Jeffrey S. Hoch 1,2,3,4 • Jaclyn Beca 1,2,3 • Mona Sabharwal 5 • Scott W. Livingstone 6 Anthony L. A. Fields 7 The Author(s) 2015. This article is published with open access at Springerlink.com ‘‘What our health-care systems need to do with their limited budgets is maximize value and no dimensions of health … will be a good measure of value because people consider other aspects in their evaluations … We must back out of the dead end that is pursuing overall efficiency’’ [1]. 1 Introduction We are grateful for the opportunity to comment on the results of McDonald et al. [2]. In this note, we summarize their findings, build on their interpretations, and suggest future directions for researchers interested in improving a health technology assessment (HTA) process. 2 Summary of the Findings McDonald et al. searched for reasons why Canada and other countries might separate their cancer drug HTA process. They appraised whether any of the rationales they & Jeffrey S. Hoch jeffrey.hoch@utoronto.ca Pharmacoeconomics Research Unit, Cancer Care Ontario, Toronto, ON, Canada Jaclyn Beca becaj@smh.ca Canadian Centre for Applied Research in Cancer Control (ARCC), Toronto, ON, Canada Mona Sabharwal monas@cadth.ca Institute for Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada Scott W. Livingstone scott.livingstone@saskcancer.ca Pan-Canadian Oncology Drug Review (pCODR), Canadian Agency for Drugs and Technologies in Health (CADTH), Toronto, ON, Canada Saskatchewan Cancer Agency, Saskatoon, SK, Canada University of Alberta, 11560 University Ave NW, Edmonton, AB T6G 1Z2, Canada Anthony L. A. Fields afields@ualberta.ca found were derived from the assumption commonly made by health economists that ‘‘the goal of society or decision makers is to maximize the total aggregate health benefit conferred to a population for a given level of resources’’. They found that this rationale was not used by Canada or any country to support the use of a separate HTA process for cancer drugs. The researchers were also not able to find another country besides Canada that had a separate cancer drug HTA process. These findings may seem surprising: Canada is the only country in the world that has a separate cancer drug HTA process; and McDonald et al. could find no justification based in economic theory for a separate process. To be clear, the authors reported that other countries (e.g. Den- mark, Belgium, the UK) set aside a separate budget for cancer drugs, and the authors found several ‘‘non-eco- nomic’’ rationales for Canada’s separate HTA process. There are two potential interpretations of these search re- sults: (1) the search missed something or (2) there really is no economic rationale in print for a separate cancer drug HTA process. Although their study might not be Centre for Excellence in Economic Analysis Research (CLEAR), Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada

Background Public drug plans are faced with increasingly difficult funding decisions. In Canada, the pan-Canadian Oncology Drug Review (pCODR) makes funding recommendations to the provincial and territorial drug plans responsible for cancer drugs. Assessments of the economic models submitted by pharmaceutical manufacturers are publicly reported. Objectives The main objective of this research was to identify recurring methodological issues in economic models submitted to pCODR for funding reviews. The secondary objective was to explore whether there exists any observed relationships between reported methodological issues and funding recommendations made by pCODR’s expert review committee. Methods Publicly available Economic Guidance Reports from July 2011 (inception) until June 2014 for drug reviews with a final funding recommendation (N = 34) were independently examined by two authors. Major methodological issues from each review were abstracted and grouped into nine main categories. Each issue was also categorized based on perception of the reviewer’s actions to manage it. Results The most commonly reported issues involved costing (59% of reviews), time horizon (56%), and model structure (36%). Several types of issues were identified that usually could not be resolved, such as quality of clinical data or uncertainty with indirect comparisons. Issues with costing or choice of utility estimates could usually be addressed or explored by reviewers. No statistically significant relationship was found between any methodological issue and funding recommendations from the expert review committee. Conclusions The findings provide insights that can be used by parties who submit or review economic evidence for continuous improvement and consistency in economic modeling, reporting, and decision making. Electronic supplementary material The online version of this article (doi:10.1007/s41669-017-0018-3) contains supplementary material, which is available to authorized users.

This article applies concepts from health economics to address what is the "right" amount of chemotherapy in non-curable disease. A health economics perspective is beneficial because it forces a focus on objectives and constraints. We review and apply the concepts of "Choice of Comparator", "Use of QALYs" and "Equating Marginal Benefit to Marginal Cost", demonstrating their fit for purpose when considering the optimal amount of chemotherapy for non-curable disease. Many efforts underway to improve healthcare can be viewed as applications of these key economic principles. The true value is in the concepts themselves and not in the associated calculations. Given the difference between a population and a patient perspective, different "optimal" amounts of chemotherapy may exist. For many, however, best may not be most. Optimal decisions may vary depending on whether the goal of treatment is to maximize hope or health.

Background: Aromatase inhibitor (ai) therapy has been subjected to numerous cost-effectiveness analyses. However, with most ais having reached the end of patent protection and with maturation of the clinical trials data, a re-analysis of ai cost-effectiveness and a consideration of ai use as part of sequential therapy is desirable. Our objective was to assess the cost-effectiveness of the 5-year upfront and sequential tamoxifen (tam) and ai hormonal strategies currently used for treating patients with estrogen receptor (er)–positive early breast cancer. Methods: The cost-effectiveness analysis used a Markov model that took a Canadian health system perspective with a lifetime time horizon. The base case involved 65-year-old women with tam-positive early breast cancer. Probabilistic sensitivity analyses were used to incorporate parameter uncertainties. An expected-value-of-perfect-information test was performed to identify future research directions. Outcomes were quality-adjusted life-years (qalys) and costs. Results: The sequential tam–ai strategy was less costly than the other strategies, but less effective than upfront ai and more effective than upfront tam. Upfront ai was more effective and less costly than upfront tam because of less breast cancer recurrence and differences in adverse events. In an exploratory analysis that included a sequential ai–tam strategy, ai–tam dominated based on small numerical differences unlikely to be clinically significant; that strategy was thus not used in the base-case analysis. Conclusions: In postmenopausal women with er-positive early breast cancer, strategies using ais appear to provide more benefit than strategies using tam alone. Among the ai-containing strategies, sequential strategies using tam and an ai appear to provide benefits similar to those provided by upfront ai, but at a lower cost.

Background Current treatment of diffuse-large-B-cell lymphoma (DLBCL) includes rituximab, an expensive drug, combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Economic models have predicted rituximab plus CHOP (RCHOP) to be a cost-effective alternative to CHOP alone as first-line treatment of DLBCL, but it remains unclear what its real-world costs and cost-effectiveness are in routine clinical practice. Methods We performed a population-based retrospective cohort study from 1997 to 2007, using linked administrative databases in Ontario, Canada, to evaluate the costs and cost-effectiveness of RCHOP compared to CHOP alone. A historical control cohort (n = 1,099) with DLBCL who received CHOP before rituximab approval was hard-matched on age and treatment intensity and then propensity-score matched on sex, comorbidity, and histology to 1,099 RCHOP patients. All costs and outcomes were adjusted for censoring using the inverse probability weighting method. The main outcome measure was incremental cost per life-year gained (LYG). Results Rituximab was associated with a life expectancy increase of 3.2 months over 5 years at an additional cost of $16,298, corresponding to an incremental cost-effectiveness ratio of $61,984 (95% CI $34,087‒$135,890) per LYG. The probability of being cost-effective was 90% if the willingness-to-pay threshold was $100,000/LYG. The cost-effectiveness ratio was most favourable for patients less than 60 years old ($31,800/LYG) but increased to $80,600/LYG for patients 60–79 years old and $110,100/LYG for patients ≥80 years old. We found that post-market survival benefits of rituximab are similar to or lower than those reported in clinical trials, while the costs, incremental costs and cost-effectiveness ratios are higher than in published economic models and differ by age. Conclusions Our results showed that the addition of rituximab to standard CHOP chemotherapy was associated with improvement in survival but at a higher cost, and was potentially cost-effective by standard thresholds for patients

We congratulate Amdahl et al.1 on publishing their paper about the cost-effectiveness of pazopanib compared with sunitinib in metastatic renal cell carcinoma (mrcc) in Canada. The article reports an analysis similar to the one submitted to the pan-Canadian Oncology Drug Review to support the funding request for pazopanib in mrcc, updated with final overall survival (os) data from the pivotal trial2. Economic evaluations in oncology are increasingly important to guide both policy and practice. We commend the efforts of these authors to put their submitted analyses into the public domain for transparency and to support and inform future research. The base-case analysis (using the list prices of pazopanib and sunitinib) by Amdahl et al.1 found that, compared with sunitinib, which is the standard of care for first-line therapy in mrcc, first-line pazopanib is likely cost-saving. The base case analysis also suggested that pazopanib might be slightly more effective than sunitinib numerically, with an incremental gain of 0.057 life-years and 0.059 quality-adjusted life-years. Before concluding that pazopanib is dominant (that is, it provides more benefit for a lower cost) with respect to sunitinib, it is important to review the clinical data comparing pazopanib and sunitinib in mrcc to assess the comparative efficacy and preference-based measures of health-related quality of life (hrqol) associated with those agents—that is, their health utilities—to examine the face validity of the economic model in its base case. The efficacy differences between the pazopanib and sunitinib in the comparz study3 were not statistically significant, median progression-free survival for pazopanib and sunitinib being 8.4 months [95% confidence interval (ci): 8.3 to 10.9 months] and 9.5 months (95% ci: 8.3 to 11.1 months) respectively, with a hazard ratio of 1.05 (95% ci: 0.90 to 1.22). The study met its primary endpoint of non-inferiority in progression-free survival. No os difference was observed in the comparz study, in which median os was 28.4 months for pazopanib (95% ci: 26.2 to 35.6 months) and 29.3 months for sunitinib (95% ci: 25.3 to 32.5 months), with a hazard ratio of 0.91 (95% ci: 0.76 to 1.08). At the updated analysis, os was similar in the two groups (hazard ratio for pazopanib vs. sunitinib: 0.92; 95% ci: 0.79 to 1.06; p = 0.24)2. With similar survival results for pazopanib and sunitinib based on the comparz study, one might ask, “How did the model project an incremental gain of 0.057 life-years in favour of pazopanib?” The model actually projected a shorter life expectancy while patients were taking pazopanib than while their counterparts were taking sunitinib (0.013 life-years lost in the progression-free state). However, the model also projected that, after patients progressed and stopped taking pazopanib, their life expectancy was longer than it was for patients who received sunitinib (0.070 life-years gained in the post-progression state). Together, the loss and the gain resulted in a net gain in life expectancy for pazopanib, implying that the survival benefit of pazopanib acted only after progression, when patients were no longer taking pazopanib. There is no biologic basis for that phenomenon, and it likely simply reflects small numerical differences between the pazopanib and sunitinib progression-free survival and os curves, without accounting for uncertainty. Interestingly, the model also predicted that pazopanib would be more effective in at least 80% (or possibly all) of the simulations despite the nonsignificant result. Although the comparz study3 collected some hrqol measures, it did not collect preference-based measures of hrqol to allow for the calculation of quality-adjusted life-years for the purpose of economic evaluation. The pisces study4—a randomized, double-blind trial with a crossover design (that is, pazopanib→sunitinib vs. sunitinib→pazopanib)—had, as its primary endpoint, an examination of patient preference for either pazopanib or sunitinib, which suggested that patients preferred pazopanib over sunitinib. However, the study had a few limitations5, including a relatively high proportion of the randomly assigned patients (33%) not being evaluable for the primary endpoint, and the analysis of the pazopanib preference being based on a “modified” intention-to-treat population. The EQ-5D (EuroQoL Group, Rotterdam, Netherlands) was also collected as the preference-based measure of hrqol in the pisces study4, but the EQ-5D results would have been subject to similar limitations. The data from the pisces study were used in the submission to the pan-Canadian Oncology Drug Review. In the updated analysis1, the authors conducted a regression based on patients in a trial comparing pazopanib with placebo6, assuming that the effect of adverse events (aes) were driving the differences in hrqol, regardless of actual treatment received. For the analysis, the aes were grouped by severity and whether the aes were more commonly occurring in the sunitinib or the pazopanib group of the comparz trial. Using that approach, the regression model found that the health utility decrement was larger for the group of aes more commonly occurring in patients who used sunitinib than for the remaining aes more frequently occurring in patients who used pazopanib in the comparz trial. The results of the regression model were combined with the incidence and duration of aes in each treatment arm to derive the mean utility values used in the model, producing mean utility values of 0.7089 (standard error: 0.0193) for pazopanib and 0.6832 (standard error: 0.0236) for sunitinib, an incremental difference of 0.0257 in the progression-free period1. Given that the comparz trial demonstrated similar efficacy and a more favourable toxicity profile for pazopanib, it is not unreasonable that the point estimate of the utility score could slightly favour the pazopanib group. However, these mean utility values were not directly derived and might be neither statistically nor clinically different, especially because the difference was smaller than the reported estimates of minimal important differences for health utilities (which are in the range of 0.05–0.08 for the EQ-5D)7,8. Thus, it is somewhat difficult to conclude from those data that pazopanib is associated with better utility than sunitinib. It might be reasonable to conservatively expect that the utilities of pazopanib and sunitinib are fairly similar given the size of the standard errors of the two utilities, subject to a reasonable amount of uncertainty9,10. Given that clinical trials did not demonstrate a statistically significant survival benefit or EQ-5D health utility benefit for pazopanib over sunitinib, we feel that an appropriate interpretation could be that the study findings suggest similar efficacy and health utility for the two drugs. Reasonably, the pan-Canadian Oncology Drug Review’s Expert Review Committee also concluded that it is reasonable to assume similar efficacy and to focus on the cost comparison between pazopanib and sunitinib in this setting11. We appreciate that the sensitivity analyses by Amdahl et al.1 address all the considerations discussed here, including the importance of the relative price of the two drugs. The authors demonstrate as part of their additional analyses that—assuming similar efficacy, health utility, and daily price of the two therapies—only minor cost differences remain. Thus, interpreting the analyses in light of the evidence, it appears that these two options for first-line therapy in mrcc might be largely similar and, taking into account the relative prices of the two drugs, the hope would be that, after confidential negotiations, they will also be similar in cost. In that case, having both drugs available would give patients the option to choose based on individual preference and side effect profile, especially in the case of intolerance to one of the drugs, and would ensure that health care resources are being efficiently used. The generalizability of the study findings remains to be seen in practice. Verification from experience is needed to know whether the comparative outcomes as laid out will be realized. In Canada, jurisdictions have an important opportunity and challenge to evaluate the real-world effectiveness and cost-effectiveness of therapies in clinical practice after drugs are funded. Moreover, post-market research can provide valuable insights into practice patterns when two alternatives are funded and can possibly inform continued uncertainties such as sequencing and long-term adverse effects. We applaud the approach of the authors to share their analyses with the broader clinical and research communities, and we encourage more authors of economic evaluations created and submitted to review bodies (for example, the Canadian Agency for Drugs and Technologies in Health, the pan-Canadian Oncology Drug Review) to follow suit. We expect that this activity will build on the principle of transparency being increasingly championed by the review organizations and will improve the rigour of the economic evidence used to inform policy. Finally, we call on the community to continue to pursue both academic merit and clinical and policy relevance by supporting the availability of peer-reviewed publications of economic evaluations to inform the reimbursement review process. Ideally, it would be helpful if economic evaluations were to be published before decision-making so as to engage more stakeholders in the discussion12. In doing so, the clinical and economic evidence bases supporting the health technology assessment processes in Canada might be brought into better alignment, improving the robustness of decision-making and ultimately helping health care systems in Canada to provide effective and appropriate care to patients.

Discussion “Continuing benefits” may overestimate and “observed benefits” underestimate effects of new treatment. Many ways to model “diminishing benefits”: • Equal hazard rates? • Look for equal time in progressed state? Other questions: How and when do risks change? Changing risk of progression as well as death? Difference Variable PFS Progressed OS Survival curves Exponential -Lognormal New drug cost $6,000 $1,500 -Comparator cost $2,000 $1,500 -Utility 0.8 0.5

Background Primary care provides most of the evidence-based chronic disease prevention and screening services offered by the healthcare system. However, there remains a gap between recommended preventive services and actual practice. This trial (the BETTER Trial) aimed to improve preventive care of heart disease, diabetes, colorectal, breast and cervical cancers, and relevant lifestyle factors through a practice facilitation intervention set in primary care. Methods Pragmatic two-way factorial cluster RCT with Primary Care Physicians’ practices as the unit of allocation and individual patients as the unit of analysis. The setting was urban Primary Care Team practices in two Canadian provinces. Eight Primary Care Team practices were randomly assigned to receive the practice-level intervention or wait-list control; 4 physicians in each team (32 physicians) were randomly assigned to receive the patient-level intervention or wait-list control. Patients randomly selected from physicians’ rosters were stratified into two groups: 1) general and 2) moderate mental illness. The interventions involved a multifaceted, evidence-based, tailored practice-level intervention with a Practice Facilitator, and a patient-level intervention involving a one-hour visit with a Prevention Practitioner where patients received a tailored ‘prevention prescription’. The primary outcome was a composite Summary Quality Index of 28 evidence-based chronic disease prevention and screening actions with pre-defined targets, expressed as the ratio of eligible actions at baseline that were met at follow-up. A cost-effectiveness analysis was conducted. Results 789 of 1,260 (63%) eligible patients participated. On average, patients were eligible for 8.96 (SD 3.2) actions at baseline. In the adjusted analysis, control patients met 23.1% (95% CI: 19.2% to 27.1%) of target actions, compared to 28.5% (95% CI: 20.9% to 36.0%) receiving the practice-level intervention, 55.6% (95% CI: 49.0% to 62.1%) receiving the patient-level intervention, and 58.9% (95% CI: 54.7% to 63.1%) receiving both practice- and patient-level interventions (patient-level intervention versus control, P < 0.001). The benefit of the patient-level intervention was seen in both strata. The extra cost of the intervention was $26.43CAN (95% CI: $16 to $44) per additional action met. Conclusions A Prevention Practitioner can improve the implementation of clinically important prevention and screening for chronic diseases in a cost-effective manner.