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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.

Background Although increasing evidence has suggested that an efficacy-effectiveness gap exists between clinical trial (CT) and real-world evidence (RWE), to the authors' knowledge, the magnitude of this difference remains undercharacterized. The objective of the current study was to quantify the magnitude of survival and toxicity differences between CT and RWE for contemporary cancer systemic therapies. Methods Patients receiving cancer therapies funded under Cancer Care Ontario's New Drug Funding Program (NDFP) were identified. Landmark CTs with data regarding survival and adverse events (AEs) for each drug indication were identified. RWE for survival and hospitalization rates during treatment were ascertained through Canadian population-based databases. The efficacy-effectiveness gap for each drug indication was calculated as the difference between RWE and CT data for median overall survival (OS), 1-year OS, and generated hazard ratios (HRs) with 95% CIs from Kaplan-Meier OS curves. Toxicity differences were calculated as the difference between RWE of hospitalization rates and CT serious AE rates. Results Twenty-nine indications from 20 systemic therapies were included. Twenty-eight of 29 indications (97%) demonstrated worse survival in RWE, with a median OS difference of 5.2 months (interquartile range, 3.0-12.1 months). Lower effectiveness in RWE also was demonstrated through a meta-analysis of an OS hazard ratio of 1.58 (95% CI, 1.39-1.80). The median difference between RWE for hospitalization rates and CT serious AEs was 14% (95% CI, 9%-22%). Conclusions An efficacy-effectiveness gap exists for contemporary cancer systemic therapies, with a 5.2-month lower median OS observed in RWE compared with CT data. These data supports the use of RWE to better inform real-world decision making regarding the use of cancer systemic therapies.

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.

Aims To examine the real-world safety of adding bevacizumab to first-line irinotecan-based chemotherapy for patients with metastatic colorectal cancer (mCRC). Materials and methods Patients diagnosed with CRC in three Canadian provinces (Ontario, Saskatchewan and British Columbia) who received publicly funded bevacizumab and/or irinotecan from 2000 to 2016 were identified from cancer registries. Propensity score 1:1 matching (PSM) and inverse probability of treatment weighting (IPTW) were performed to contemporaneous and historical controls, adjusting for baseline demographic and clinical characteristics. Safety end points evaluated during first-line treatment plus 30 days included mortality within 30 days and all-cause-, chemotherapy- and bevacizumab-related hospitalisations. Chemotherapy- and bevacizumab-related visits were defined as hospitalisations for specific conditions commonly associated with chemotherapy (e.g. infections) or bevacizumab (e.g. arteriovenous thromboembolism) using most responsible diagnosis codes. In PSM and IPTW-weighted cohorts, we assessed event frequencies using odds ratios from logistic regressions and event rate ratios using negative binomial regression models. The results from each province and comparison were pooled using random-effects meta-analysis. Results We identified 16 250 mCRC patients who received first-line irinotecan-based treatment. In PSM cohorts, bevacizumab was associated with fewer deaths within 30 days of treatment compared with contemporaneous (pooled odds ratio = 0.62; 95% confidence interval 0.50–0.75) and historical controls (pooled odds ratio = 0.73; 95% confidence interval 0.58–0.93). Hospitalisations were more frequent among patients treated with bevacizumab compared with historical controls but similar to contemporaneous controls. As patients receiving bevacizumab were exposed to a longer average treatment duration, across their full treatment duration, patients receiving bevacizumab had significantly lower rates of hospitalisations (contemporaneous pooled rate ratio = 0.56; 95% confidence interval 0.47–0.67; historical pooled rate ratio = 0.73; 95% confidence interval 0.56–0.95). Similar trends were observed for chemotherapy- and bevacizumab-related hospitalisations and in IPTW-weighted cohorts. Discussion We did not observe any increase in rates of hospitalisation or death within 30 days of treatment among mCRC patients treated with bevacizumab plus chemotherapy versus chemotherapy alone; these findings should be interpreted with caution due to the risk of residual confounding.

Cabazitaxel is used to treat patients with metastatic castration-resistant prostate cancer progressing after docetaxel. It is prepackaged in 60 mg single-dose vials, a quantity much higher than the average prescribed dose, which leads to, substantial drug wastage (DW) and associated costs. To minimize DW we implemented a cost-saving, cohorting strategy where multiple patients scheduled to receive cabazitaxel (at a dose of 20mg/m2 every 3 wks) were cohorted and treated on a single weekday whenever possible. Excess drug from each vial was then saved and used for subsequent patients treated on the same day. The drug cost with cohorting was calculated from the actual number of vials used, and the drug cost without cohorting was estimated by assumingthat one vial was used per treatment. The cost of DW was determined based on the amount of drug that was discarded. All cost calculations also accounted for the discount incentives offered by Sanofi-Aventis. Over a 3-yr period, 74 patients received 402 treatments of cabazitaxel. Multiple patients were treated on 67.4% of the treatment days, and grouping of three patients on one day saved one vial. The estimated total drug cost saved was $394 536 CAD (21.1%). Pending further studies on safety and efficacy, this strategy could potentially be adopted to mitigate DW for cabazitaxel and similarly for other oncology drugs. This would significantly decrease the overall financial burden on patients, institutions, and stakeholders. PATIENT SUMMARY: Cabazitaxel chemotherapy is associated with substantial drug wastage and associated costs. By cohorting patients scheduled to receive cabazitaxel on a single weekday, the total drug cost was decreased by $394 536 CAD (21.1%) over a 3-yr period. Similar strategies could be considered to overcome the prohibitory costs associated with drug wastage for cabazitaxel and other cancer drugs.

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.

The International Extranodal Lymphoma Study Group-32 (IELSG32) randomized patients with primary central nervous system lymphoma (PCNSL) for induction treatment with methotrexate-cytarabine, methotrexate-cytarabine-rituximab, or methotrexate-cytarabine-thiotepa-rituximab (MATRix) and reported significantly improved complete remission with the MATRix regimen. This study assessed cost-effectiveness among these three induction strategies for PCNSL. A Markov model was developed based on the IELSG32 trial over a 20 year time horizon from the Canadian health care system perspective. Costs for induction, consolidation, inpatient treatment administration, follow-up, adverse events, relapsed disease, and palliative care were included. Methotrexate-cytarabine-rituximab was subject to extended dominance by the other two strategies. The MATRix regimen compared to methotrexate-cytarabine produced 3.05 quality-adjusted life year (QALY) gains at added costs of $75,513, resulting in an incremental cost-effectiveness ratio of $24,758/QALY gained. The MATRix regimen was the optimal strategy in the majority of simulations (98% probability at willingness-to-pay of $50,000/QALY gained) and results appeared robust across sensitivity analyses.

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.

The aim of this study was to use Microsoft Excel spreadsheet software to fit parametric survival distributions. We also explain the differences between individual patient data (IPD) and survival data reconstructed in Excel and SAS. Three sets of patient data on overall survival were compared using different methods: ‘original’ IPD, ‘reconstructed SAS’, and ‘reconstructed Excel’. The best-fit distribution was selected using visual observation, supported by linear plots of predicted probabilities, goodness-of-fit coefficients, and the sum of squared error of prediction. Outcomes included the incremental cost-effectiveness ratio (ICER), incremental net benefit (INB), incremental cost, and life-years gained over short-term and lifetime horizons. These were compared for different data sets. In this example, log-normal, log-logistic, and Weibull distributions showed best-fit with the visual tests and goodness-of-fit statistics. Weibull and exponential distributions showed significant differences compared with IPD data. Data on short-term (5 years) time horizons produced by different data re-creation methods showed closeness with data reconstructed from SAS. The ICER and INB results were dependent on the time horizon and selected parametric distribution from the model. Different approaches used in fitting parametric survival distributions yielded predicted probabilities that substantially differed from those using original IPD. Our study highlights the importance of following guidelines for economic evaluations with a systematic approach to parametric survival analysis techniques in order to select best fitting parametric survival distributions.

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.

The association between obesity and survival in non-Hodgkin lymphoma is unclear. Using the Ontario Cancer Registry we conducted a retrospective analysis of incident cases of aggressive-histology B-cell lymphoma treated with a rituximab-containing regimen with curative intent between 2008-2016. 6246 patients were included. On multivariable analysis the rate of all-cause mortality was lower for the overweight body mass index (BMI 25-29.9 kg/m

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

Cost-effectiveness evidence is increasingly considered in the reimbursement decisions of pharmaceuticals. In some jurisdictions such as the UK and Canada, pharmaceutical manufacturers are required to submit economic evaluations when seeking reimbursement. Our objectives were to describe the role of economic evidence in the cancer drug review process in Canada, and to investigate the nature of problems encountered in the review and interpretation of economic evidence used in the process. We conducted a retrospective review of cancer drug review meeting minutes and reviewers’ comments on pharmacoeconomic studies submitted to the oncology drug review process in Canada. We used pharmacoeconomic reviewers’ reports and relevant cancer drug review expert advisory committee meeting minutes during the first year of the review process (April 2007 to March 2008). Fifteen economic submissions were reviewed. One-third of the studies had flaws significant enough that the advisory committee could not determine the cost effectiveness of the drugs from the results. The common issues outlined by the reviewers and committee were related to the uncertainty of comparative clinical benefits, quality of life and costs. The reviewers felt that few analyses provided sufficient sensitivity analyses around key variables to assess the robustness of results. Most problems identified by reviewers are simple to fix and do not involve advanced methods. Canada has a separate review process for making cancer drug funding recommendations, and this process uses both clinical and economic evidence. The committee could not determine the value for money of the drugs from several of the submitted pharmacoeconomic analyses. Transparent analyses and detailed critique of evidence are crucial to the use of economic evidence in reimbursement decisions. Rigorous evaluation is resource intensive and may benefit from a shared drug review process among several jurisdictions.

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

To evaluate the cost effectiveness of genetic screening for the apolipoprotein (APOE) e4 allele in combination with preventive donepezil treatment in comparison with the standard of care for amnestic mild cognitive impairment (AMCI) patients in Canada. We performed a cost-effectiveness analysis using a Markov model with a societal perspective and a time horizon of 30 years. For each strategy, we calculated quality-adjusted life-years (QALYs), using utilities from the literature. Costs were also based on the literature and, when appropriate, Ontario sources. One-way and probabilistic sensitivity analyses were performed. Expected value of perfect information (EVPI) analysis was conducted to explore the value of future research. The base case results in our exploratory study suggest that the combination of genetic testing and preventive donepezil treatment resulted in a gain of 0.027 QALYs and an incremental cost of $1,015 (in 2009 Canadian dollars [Can$]), compared with the standard of care. The incremental cost-effectiveness ratio (ICER) for the base case was Can$38,016 per QALY. The ICER was sensitive to the effectiveness of donepezil in slowing the rate of progression to Alzheimer’s disease (AD), utility in AMCI patients, and AD and donepezil treatment costs. EVPI analysis showed that additional information on these parameters would be of value. Using presently available clinical evidence, this exploratory study illustrates that genetic testing combined with preventive donepezil treatment for AMCI patients may be economically attractive. Since our results were based on a secondary post hoc analysis, our study alone is insufficient to warrant recommending APOE genotyping in AMCI patients. Future research on the effectiveness of preventive donepezil as a targeted therapy is recommended.

Aims To compare the costs and effectiveness of intensity-modulated radiotherapy (IMRT) with three-dimensional conformal radiotherapy (3DCRT) for the radical treatment of localised prostate cancer at elevated doses (>70 Gy). Materials and methods A cost-effectiveness analysis model was developed using clinical effectiveness estimates from a systematic review. The base case analysis assumes equal biochemical survival for IMRT and 3DCRT, but lower frequency of gastrointestinal toxicity for IMRT. The costs of IMRT and 3DCRT were estimated through activity-based costing, incorporating input from radiation oncologists, physicists and treatment planners. Results The delivery of IMRT produced 0.023 more quality-adjusted life-years (QALY) than 3DCRT at an additional cost of $621 (QALY and costs discounted at 5% per year), yielding an incremental cost-effectiveness ratio of $26 768 per QALY gained. The treatment cost of IMRT was $1019 more than 3DCRT, but IMRT resulted in less frequent gastrointestinal toxicity, thus avoiding $402 in the treatment of toxicity. In the scenario that compared a higher dose of IMRT (75.6 Gy) to 3DCRT (68.4 Gy), IMRT improved disease control with equal toxicity incidence, and the IMRT strategy dominated (less costly and more effective). In the base case scenario (no survival difference), the cost-effectiveness of IMRT was most sensitive to the treatment cost difference between IMRT and 3DCRT. Conclusion For radical radiation treatment (>70 Gy) of prostate cancer, IMRT seems to be cost-effective when compared with an equivalent dose of 3DCRT.

Aims Intensity-modulated radiotherapy (IMRT) is an advanced radiation technique that is particularly suited to treating head and neck cancers because it can conform a high dose to the target volume while preserving the tissue function of neighbouring structures. The objective of this study was to compare the cost and effectiveness of IMRT with three-dimensional conformal radiotherapy (3DCRT) for the treatment of locally advanced oropharyngeal cancer. Materials and methods We developed a Markov model to estimate the incremental cost per quality-adjusted life-year (QALY) gained by IMRT from the perspective of the Ministry of Health. The costs of IMRT and 3DCRT were estimated through activity-based costing, incorporating input from radiation oncologists, physicists and radiation therapists. We obtained clinical effectiveness estimates from published studies and calculated the number needed to treat to avoid a case of severe long-term xerostomia using data from a randomised controlled trial. Results The delivery of IMRT produced 0.48 more QALYs than 3DCRT at an additional cost of $2447 (QALY and costs discounted at 5% a year), yielding an incremental cost-effectiveness ratio of $5084 per QALY gained. The cost-effectiveness of IMRT was sensitive to the costs of radiotherapy and the effect of IMRT on health-related quality of life. The cost of IMRT will probably decrease with the addition of volumetric modulated arc therapy, an increasingly used technology, because volumetric modulated arc therapy reduces treatment time. We need to treat less than two patients with IMRT to avoid a case of severe, long-term xerostomia (dry mouth), and the incremental cost to avoid a case of severe, long-term xerostomia was $4532. Conclusions In the treatment of locally advanced oropharyngeal carcinoma, the IMRT strategy appears to be cost-effective when compared with 3DCRT.

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.