Economic evaluation of brentuximab vedotin for persistent Hodgkin lymphoma

Background We conducted a cost-effectiveness analysis of brentuximab vedotin for the treatment of relapsed and refractory Hodgkin lymphoma (hl) in the post–autologous stem-cell transplantation (asct) failure period, from the perspective of the Canadian health care payer. Methods We developed a decision-analytic model to simulate lifetime costs and benefits of brentuximab vedotin compared with best supportive care for the treatment of patients with hl after failure of asct. Administrative data from Ontario were used to set the model parameters. Results In the base case, treatment with brentuximab vedotin resulted in incremental quality-adjusted life-years (qalys) of 0.544 and an incremental cost of $89,366 per patient, corresponding to an incremental cost-effectiveness ratio (icer) of $164,248 per qaly gained. The icer was sensitive to the cost of brentuximab vedotin, the hazard ratio used to assess the efficacy of brentuximab vedotin treatment, and health state utilities. Conclusions In light of the available information, brentuximab vedotin has an icer exceeding $100,000 per qaly gained, which is a level often classified as having “weak evidence for adoption and appropriate utilization” in Canada. However, it is worth noting that provincial cancer agencies take into account not only the costs and associated icer, but also other factors such as a lack of alternative treatment options and the clinical benefits of expensive cancer drugs. Pricing arrangements should be negotiated, and risk-sharing agreements or patient access schemes should be explored.


INTRODUCTION
Hodgkin lymphoma (hl) is an uncommon type of cancer with an incidence of approximately 3 per 100,000 population in Canada 1 .In 2012, 940 new cases of hl were diagnosed in Canada 1 .Conventional treatment options for hl include chemotherapy, radiotherapy, and hematopoietic stem-cell transplantation.Although survival outcomes are favourable for most patients, a proportion do not experience a cure with standard treatment regimens [2][3][4] .
The standard of care for young healthy patients who relapse after front-line therapy is salvage chemotherapy, followed by high-dose therapy and autologous stem-cell transplantation (asct).Approximately 50% of patients relapse after asct 5 , and prognosis tends to be poor for those who relapse, with a short median progression-free survival 6,7 .Available treatment options for the latter group are limited, and of the available options, many are subject to the faults of being tested in nonrandomized settings.Furthermore, toxicity-and treatment-related mortality rates are high, making those treatments unattractive to hematologists and patients.Historically, third-line treatment options in patients who relapse after asct include allogeneic stem-cell transplantation, a second asct, radiation therapy, and single-agent or combination chemotherapy, all of which are ultimately palliative.The reported benefits of those therapies vary, with median survival ranging from 6 months to 30 months [8][9][10][11] .
Brentuximab vedotin (Adcetris: Seattle Genetics, Bothell, WA, U.S.A.) is a CD30-directed antibody-drug conjugate that selectively targets and kills cancer cells expressing the CD30 antigen, such as classical hl and systemic anaplastic large-cell lymphoma.Early phase i and ii clinical trials demonstrated favourable response rates and toxic effects, and promising progression-free survival rates 12,13 .The phase ii trial showed that 75% of patients achieved complete or partial remission, with a median progression-free survival of 5.6 months 12 .According to recent data from the long-term follow-up of the phase ii study, median overall survival was 40.5 months 14 .Reported treatment-related adverse events included peripheral sensory neuropathy, fatigue, nausea, neutropenia, diarrhea, and pyrexia.Approximately 20% of patients discontinued treatment because of a treatment-related adverse event.Peripheral sensory neuropathy and peripheral motor neuropathy were the most commonly reported reasons for stopping treatment.
In addition to being a third-line treatment option, brentuximab vedotin has been evaluated in ongoing clinical trials as monotherapy, as part of combination therapy in the first-and second-line settings 15 , and as postasct consolidation therapy 16 .
Brentuximab vedotin received regulatory approval for the treatment of hl after failure of asct or after failure of 2 pr ior mu lt i-agent chemot herapy reg i mens i n transplantation-ineligible patients, and also for the treatment of patients with relapsed systemic anaplastic largecell lymphoma 17 .In Canada, the pan-Canadian Oncology Drug Review recommended funding the drug for patients who relapse after asct and for patients with systemic anaplastic large-cell lymphoma, with the condition that in either case, the incremental cost-effectiveness ratio (icer) be improved to an acceptable threshold 18 .In Ontario, Cancer Care Ontario listed brentuximab vedotin as a part of the New Drug Funding Program 19 .
In light of the decision to fund brentuximab vedotin in certain clinical circumstances, we evaluated the incremental health benefits, costs, and cost-effectiveness of brentuximab vedotin treatment from the perspective of the Canadian health care payer.We developed a decision-analytic model and used the Ontario Cancer Registry, administrative databases, and published sources to set the model parameters.

Model Overview
The decision-analytic model projects the lifetime clinical and economic consequences for hl patients who receive third-line treatment after failure of asct.The model starts with a clinical decision to treat with brentuximab vedotin rather than with best supportive care [Figure 1   In the M2 model, the simulation of lifetime economic and clinical outcomes for patients receiving best supportive care includes three distinct health states: n Patient is free from treatment failure n Patient's disease progresses n Death The model assumes that peripheral sensory neuropathy is the only adverse reaction that would stop a patient from continuing treatment with brentuximab vedotin, leading to a switch from brentuximab vedotin to best supportive care.A separate health state named Treatment-Related Serious Adverse Event was incorporated into the M1 model to account for changes in treatment costs, health care utilization costs, and quality of life associated with stopping brentuximab vedotin and switching to best supportive care.
The model was developed using the TreeAge Pro Suite software application (2015 release: TreeAge Software, Williamstown, MA, U.S.A.), and it was run using a lifetime horizon with half-cycle correction.

Data and Cohort
The model was populated using data from the pivotal phase ii clinical trial 13 and by administrative and cancer registry data obtained from the Ontario Cancer Data Linkage Project ("cdlink," http://www.ices.on.ca/Research/Research-programs/ Cancer/cd-link).Cd-link is an initiative of the Ontario Institute for Cancer Research and Cancer Care Ontario's Health Services Research Program, whereby risk-reduced coded data from the ICES Data Repository managed by the Institute for Clinical Evaluative Sciences is provided directly to researchers with the protections of a comprehensive data use agreement.Cd-link connects data from the Ontario Cancer Registry with several Ontario administrative databases, including the Discharge Abstract Databases, the Ontario Health Insurance Plan (ohip), and the Ontario Drug Benefit.
Using the cancer registry, we identified 2475 patients diagnosed with hl in Ontario during 2000-2006.By linking the Ontario Cancer Registry data for those patients with the ohip database, we determined that 163 patients received second-line high-dose chemotherapy followed by asct.
The phase ii trial included only patients who experienced a failed asct, and we therefore restricted the study cohort to a similar group.Of the 163 patients who underwent asct, 77 patients who went on to receive thirdline treatment-either chemotherapy, radiation therapy, a second asct, or allogeneic stem-cell transplantation after the asct-were identified.We assumed that those patients received the additional treatment because they had relapsed after the asct.Table i summarizes the clinical characteristics of those patients.
To conduct the survival analysis, we extracted 2-year follow-up data for the patients from the ohip database and used treatment switch or re-treatment as a proxy for progression.We assumed that patients developed progression after third-line treatment if they satisfied at least 1 of the following criteria: n received chemotherapy 5 months after third-line treatment, n received chemotherapy with a difference of at least 60 days in service dates for 2 consecutive chemotherapy physician claims, n received radiation therapy, n underwent stem-cell transplantation, or n received palliative care.

Estimation of Transition Probabilities
We estimated transition probabilities for Freedom from Treatment Failure to Progression in the M2 model and for Progression to Death by fitting a Weibull distribution to patient follow-up data obtained through cd-link.We obtained transition probabilities for Improve or Remain Stable to Disease Progression in the M1 model by adjusting the Weibull progression-free survival curve fitted to the patient follow-up data retrieved from the cd-link for the hazard ratio of 0.41-an outcome of the subgroup analysis comparing the hazard for patients on brentuximab vedotin therapy after systemic therapy with the hazard for patients receiving prior systemic therapy as reported for the phase ii clinical trial.
To compute the transition probabilities beyond the 24-month follow-up period, we extrapolated the fitted Weibull survival curves.We used Ontario sex-specific life tables and the sex distribution in the phase ii trial and in the cohort obtained from cd-link to derive all-cause mortality rates.Finally, we assumed that patients who develop a treatment-related adverse event such as peripheral sensory neuropathy, and thus discontinue brentuximab vedotin treatment (M1 model), follow the same transition probability matrix as do patients in the best supportive care model (M2 model).

Cost and Utility Values
The list price of brentuximab vedotin in Canada is $4,840.00per 50 mg vial 21 .The cost of gemcitabine, which is funded through the New Drug Funding Program in Ontario, is $0.0620 per milligram.The cost of administration was estimated from the internal costing database at the London Regional Cancer Program in London, Ontario.
We estimated hospitalization costs using resource intensity weights recorded in the Discharge Abstract Database and the cost per weighted case obtained from the annual report of hospital financial performance indicators released by the Canadian Institute for Health Information 22 .Physician costs were estimated from the ohip database, and drug costs were obtained from the Ontario Drug Benefit database.
Several studies have reported health state utilities and health-related quality of life measures in connection with treatment outcomes and toxicities for patients with relapsed and refractory hl [23][24][25][26][27] .In the base case, we assumed that brentuximab vedotin neither improves nor worsens quality of life; thus, quality of life would be the same for the Improve or Stable and Free From Treatment Failure states.According to the published literature, long-term quality of life for persistent hl after high-dose chemotherapy plus asct is 0.8 28 .We also assumed that quality of life is decremented by 10% when a patient with hl relapses after third-line treatment 28 .Finally, we assumed that patients developing peripheral sensory neuropathy would have the same quality of life as an individual with breast cancer developing the same adverse reaction 29 .
Costs were converted to 2012 Canadian dollars using the health and personal care consumer price index 30 .All costs and benefits were discounted at 5% according to Canadian guidelines 31 .

Base-Case Scenario
In the base case, brentuximab vedotin treatment resulted in an average incremental utility of 0.544 quality-adjusted life-years (qalys) per person and an average incremental cost of $89,366 per person, which resulted in an icer of $164,248 per qaly gained.

Sensitivity Analyses
We conducted a number of sensitivity and scenario analyses.The icer was sensitive to several model input parameters (Table ii).When the probability of developing peripheral sensory neuropathy dropped to 1% compared with 5.8% in the base case, the icer decreased to $69,540 per qaly gained.The icer fell to $121,092 per qaly gained if patients on brentuximab vedotin treatment had perfect health (utility of 1) rather than 0.8 as was assumed in the base case.
When patients receiving best supportive care with no evidence of progression had a utility of 0.6, rather than 0.8 as was assumed in the base case, the icer became $100,476 per qaly gained.When no discounting was in effect, the icer dropped to $122,040 per qaly gained.The model outcomes were relatively robust to changes in other parameters such as the cost of brentuximab vedotin administration, chemotherapy cycle, pre-and post-progression health care utilization, transition probabilities, and utility of progression (Table ii).
We conducted sensitivity analyses on the price of brentuximab vedotin and the relative survival advantage of brentuximab vedotin compared with best supportive care.When the cost of brentuximab vedotin was reduced by approximately 80%, the icer was less than $50,000 per qaly gained.The icer fell below $100,000 per qaly gained if the daily cost of the drug was lowered by approximately 45% and below $150,000 per qaly gained when the daily cost was lowered by more than 10%.The icer fell to $129,420 per qaly gained when the hazard ratio was 0.1.In 2-way sensitivity analyses, when the drug cost was lowered by 45% and the hazard ratio was below 0.41, the icer fell below $100,000 per qaly gained (Figure 2).
In probabilistic sensitivity analyses, we simultaneously sampled from distributions defined for all key parameters (Table iii).In all observations, the icer was greater than $50,000 per qaly gained.Approximately 17% of the icers were below the $100,000, 43% were below the $150,000, and 85% were below the $200,000 per qaly gained thresholds [Figure 3(A)].Brentuximab vedotin treatment becomes equally preferred to best supportive care at a willingness to pay of $162,000 per qaly gained [Figure 3(B)].

DISCUSSION
We developed a decision-analytic model to investigate the cost-effectiveness of brentuximab vedotin compared with best supportive care for the treatment of patients with hl who relapse after asct, from the perspective of the Canadian health care payer.In the base case, brentuximab vedotin resulted in an incremental cost of $89,366 and an incremental effect of 0.544 qalys, corresponding to an icer of $164,248 per qaly gained.That icer estimate is higher than the $100,000 per qaly gained that is often interpreted as having "weak evidence for adoption and appropriate utilization" 33 .Our estimate is also higher than the icer of $111,752 per qaly gained submitted by the manufacturer in the original submission to the pan-Canadian Oncology Drug Review 21 .
The cost-effectiveness of brentuximab vedotin has already been explored in several jurisdictions around the world [34][35][36][37][38] .In the United Kingdom, the National Institute for Health and Care Excellence concluded that brentuximab vedotin was not cost-effective at a given price and efficacy 39 .To the best of our knowledge, our economic analysis is the first Canadian study to use clinical practice data to establish the cost-effectiveness of brentuximab vedotin.In the study, we adapted brentuximab vedotin to the Canadian cancer treatment setting with the aid of both published data and Canadian administrative databases, which makes our analysis different from those in other published international studies.
Targeted therapies in general tend to have high icers.For example, an economic evaluation of adding bevacizumab to paclitaxel and carboplatin for the treatment of ovarian cancer resulted in an icer of $479,712 per life-year gained 40 .The addition of cetuximab to platinum-based chemotherapy for the first-line treatment of recurrent or metastatic headand-neck cancer resulted in an icer of $386,000 per qaly gained 41 .Bevacizumab in combination with paclitaxel in the first-line treatment of patients with metastatic breast cancer yielded an icer of $745,000 per qaly gained 42 .Denosumab compared with zoledronic acid in the management of skeletal metastases secondary to breast cancer resulted in an icer of $697,499 per qaly gained 43 .
We conducted pricing scenarios and found that a price reduction of at least 45% would be needed for the icer to reach less than $100,000 per qaly gained.In sensitivity analyses, the icer was sensitive to the hazard ratio resulting from comparing progression-free survivals for brentuximab   vedotin and for best supportive care.Considering the challenges of conducting randomized phase iii clinical trials in patients with hl who relapse after asct, the present study provides valuable insight into the cost-effectiveness of brentuximab vedotin based on phase ii data.
At the time that our study was conducted, brentuximab was the only promising treatment option for patients who relapse after asct.As novel drugs with activity in hl become available, one example being the PD-1 inhibitor nivolumab 44 , the order of salvage treatments for patients in the relapsed and refractory setting could change, which could clearly affect our model.
Our study has several limitations.First, the hazard ratio was based on a comparison of the hazard for a subgroup of patients who received brentuximab vedotin after systemic therapy and the hazard for the same group of patients on the preceding systemic therapy in a nonrandomized phase ii trial; our estimate might therefore have considerable uncertainty, given that the latter setting differs from the setting used in our economic analysis.Second, our definition of progression in the data analysis is a proxy, given that it is based on treatment switch, which might not necessarily reflect a true relapse.In practice, progression is verified by diagnostic procedures such as imaging by computed tomography or positron-emission tomography, and a biopsy.Also, considering that Guadagnolo et al. 28 served as the primary source for the utilities, there could be uncertainty in the baseline utility values, which were extensively tested in sensitivity analyses.Finally, like the administrative data used in any study, our data might contain coding errors that could affect the results.One specific example is the lack of chemotherapy treatment reported before asct for 1 of the 77 patients in the ohip database (most likely a fee-for-service code entry error).

CONCLUSIONS
In the base-case scenario, the icer for brentuximab vedotin was $164,248 per qaly gained.That icer might not represent "good value for money" based on commonly accepted cost-effectiveness standards.However, reimbursement decisions must take into account not only the cost, effectiveness, and associated icer of a new treatment, but also other factors such as burden of disease and lack of effective alternative treatment options.A risk-sharing agreement or patient access scheme could help to reduce the costper-patient burden to the health care payer and ensure appropriate medical care utilization 45 .opinions, results, and conclusions reported in this paper are those of the authors.No endorsement by ices, cco, the Government of Ontario, or oicr is intended or should be inferred.Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information (cihi).However, the analyses, conclusions, opinions, and statements expressed herein are those of the authors and not necessarily those of cihi.

ACKNOWLEDGMENTS
Funding was provided by an academic development grant from Western University.The funding sources had no role in the design or conduct of the study evaluating the cost-effectiveness of brentuximab vedotin; in the collection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.

CONFLICT OF INTEREST DISCLOSURES
We have read and understood Current Oncology's policy on disclosing of conflicts of interest, and we declare that we have none.

AUTHOR AFFILIATIONS
(A)].Two distinct Markov models represent the decision alternatives: M1 models treatment with brentuximab vedotin, and M2 models the provision of best supportive care [Figure 1(B,C)].In the base-case scenario, M2 uses single-agent gemcitabine 20 as the best supportive care agent.In the M1 model, the simulation of lifetime costs and benefits for patients receiving brentuximab vedotin treatment includes four health states: n Patient shows improvement or remains stable n Patient develops a treatment-related serious adverse event that prevents continuation of treatment n Patient's disease progresses n Death

b
One-time physician visit is assumed upon development of peripheral sensory neuropathy.c Includes hospitalization and physician and drug costs.ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life-year.

FIGURE 2
FIGURE 2 Sensitivity of the incremental cost-effectiveness ratio (ICER) to the hazard ratio and price (per milligram) of brentuximab vedotin.QALY = quality-adjusted life-year.
This study was supported through provision of data by the Institute for Clinical Evaluative Sciences (ices) and Cancer Care Ontario (cco), and through funding support to ices from an annual grant by Ontario's Ministry of Health and Long-Term Care and the Ontario Institute for Cancer Research (oicr).The

b
Hourly cost for pharmacy preparation time is $43.29 and for infusion time is $112.15.c Includes cost of consultation visit.d Administered on day 1 and day 8 of the 21-day treatment cycle.Calculation: $0.0620 (gemcitabine price per milligram) × 1.79 m 2 (assumed body surface area) × 800 mg/m 2 (dose) × 4 (infusions in month) = $355.14.e Maintained by the Canadian Institute for Health Information.f Parameters of β distributions are integers.g Peripheral sensory neuropathy is an adverse event that stops treatment continuation.Median time to resolution is 13.2 weeks.pCODR = pan-Canadian Oncology Drug Review.

TABLE II
Summary of one-way sensitivity analyses a Administration cost includes costs of pharmacy preparation time and infusion time.
*Telfer School of Management, University of Ottawa, Ottawa, ON; † Ivey Business School, Western University, London, ON; ‡ Department of Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, and § Department of Medicine, Division of Hematology, Schulich School of Medicine and Dentistry, Western University, London, ON.