• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

PubMed Health. A service of the National Library of Medicine, National Institutes of Health.

Picot J, Cooper K, Bryant J, et al. The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation. Southampton (UK): NIHR Journals Library; 2011 Dec. (Health Technology Assessment, No. 15.41.)

5Economic analysis

Introduction

The aim of this section is to assess the cost-effectiveness of first-line treatments for people with MM, who are ineligible for HDT with SCT, compared with existing treatments. The economic evaluation comprises:

Systematic review of existing cost-effectiveness evidence

Methods for the systematic review of cost-effectiveness

A systematic literature search was undertaken to identify economic evaluations for first-line treatment with either bortezomib or thalidomide in combination with an alkylating agent and a corticosteroid in people with MM, who are ineligible for HDT with SCT, compared with existing treatments. The details of the search strategy and the methods for the systematic review of cost-effectiveness studies are outlined in Chapter 3 and Appendix 1.

Results of the systematic review of cost-effectiveness

Searches for economic evaluations identified the titles and abstracts of 183 potentially relevant studies. The full text of seven papers was retrieved for further consideration, with none of the studies meeting the a priori inclusion criteria. A summary of the selection process and the reasons for exclusion are presented in Figure 5 and a list of excluded studies is presented in Appendix 8. Two studies were excluded as they assessed a different intervention and/or population group from that specified in the research protocol.70,71 Although five studies reported as abstracts appeared to meet the a priori inclusion criteria,7276 they did not contain sufficient information on the methods used and the results to justify formal data extraction or critical appraisal. Given the apparent relevance of these five studies, a brief summary of the abstracts is presented below.

FIGURE 5. Flow chart of identification of studies for inclusion in the review of cost-effectiveness.

FIGURE 5

Flow chart of identification of studies for inclusion in the review of cost-effectiveness. a The five abstracts provided insufficient details of methods and results to allow inclusion in a formal systematic review. However, as the abstracts met other (more...)

Deniz and colleagues72 estimated the lifetime health and cost consequences of MPT compared with MP in people in Scotland with previously untreated MM. They developed a Markov model for a cohort of patients receiving a course of MPT or MP, conceptualising the disease by four health states: preprogression without AE, preprogression with AE, progressive disease and death. Progression between health states as well as treatment duration, dose and AE risks were derived from a long-term RCT (see Chapter 4, Results of the systematic review of clinical effectiveness).23 Patient cohorts received a maximum of 12 six-week cycles of treatment, until progression or treatment-limiting toxicity. The abstract indicates that health-state utilities associated with disease states and AEs were obtained from the literature, but no sources are provided. Thalidomide costs were from UK list prices and routine disease management costs reflected current practice in Scotland. Costs and health outcomes were discounted at 3.5% per annum. The model estimated improvements in health outcomes with MPT with a median TTP of 25 months versus 12 months with MP. Estimated median OS was 4.03 years with MPT versus 2.88 years with MP. These translated to a gain of 0.91 QALYs for MPT (3.24 QALYs) compared with MP (2.32 QALYs). There were increased costs with MPT of £25,199 per patient compared with £8935 per patient for MP, leading to an incremental cost-effectiveness ratio (ICER) of £17,847 per QALY and £14,803 per life-year gained. The authors state that sensitivity analyses showed that these results were consistent through changes in model parameters, although no information is presented. The authors conclude that MPT improves PFS and OS compared with MP and the results are cost-effective. A similar study comparing lifetime health and cost consequences of MPT compared with MP was completed for untreated MM patients in Wales.74 While this evaluation used the same clinical outcomes for OS and PFS, it used slightly different QALY gains (0.9 QALYs) and lifetime costs specific to managing the disease in Wales (£16,937 per patient for MPT vs £1524 per patient for MP). The study produced a slightly more favourable ICER of £17,002 per QALY and £13,346 per life-year gained. It was reported that sensitivity analyses showed that findings were robust, with 95% of outcomes between £12,750 and £26,500 per QALY gained. Both studies were funded by the manufacturer of thalidomide.

De Abreu Lourenco and colleagues75 assessed whether MPT was cost-effective compared with MP for people in Australia who had been newly diagnosed with MM as part of an application to the Pharmaceutical Benefits Advisory Committee (PBAC). They extrapolate Kaplan–Meier survival curves from an unspecified Phase III study to a lifetime horizon to estimate the mean survival time. Costs included drugs, medical services and treatment for thalidomide-related AEs. These data were incorporated into a cost-effectiveness analysis adopting an Australian health-care system perspective, with costs and benefits discounted at 5% (AUS$2008). The modelled analysis estimated an incremental gain in average survival of 1.47 years and 1.14 QALYs with an associated average incremental cost of AUS$23,953. This results in an ICER of AUS$20,998. The authors concluded that the analysis had resulted in a positive recommendation from PBAC to fund thalidomide for the treatment of patients newly diagnosed with myeloma.

Yoong and colleagues73 estimated the cost-effectiveness of bortezomib in combination with MP (VMP) compared with MP and MPT in previously untreated people with MM in Canada who are unsuitable for SCT. Clinical outcomes originated from the VISTA study26 for VMP compared with MP and from an unspecified indirect comparison of VMP and MPT. The economic model projected OS over a 10-year horizon for VMP, MP and MPT using data from relevant studies and survival HRs. Resource use data included costs of drugs, outpatient cancer clinic, management of AEs, supportive care and subsequent lines of treatment, although sources were not specified. The discounted QALYs were 3.51 for VMP, 2.84 for MP and 3.29 for MPT. The total cost of treatment per patient was CAN$59,117 for VMP, CAN$27,026 for MP and CAN$52,226 for MPT. The ICER for VMP versus MP was CAN$48,294 per QALY gained, and it was CAN$31,975 per QALY gained for VMP versus MPT. The study states that sensitivity analyses showed that survival difference was the most influential factor. The authors concluded that the VMP regimen indicates good value for money, and it is being adopted by public cancer agencies in Canada.

Wang and colleagues76 also compared the cost-effectiveness of VMP, MPT and MP as first-line therapy for people with MM in the USA who were ineligible for autologous SCT. A lifetime (20 years) Markov model from the US payer's perspective was developed with seven health states respresenting periods of treatment response (stable disease/MR, PR or CR), treatment-free interval, progressive disease, second-line treatment and death. Monthly transition probabilities were estimated from the VISTA trial data for VMP and MP,26 and from the IFM 99/06 trial for MPT.23 Costs included drug and medical costs, treatment-related AEs, second-line treatment and resource utilisation during treatment-free intervals and progressive disease. All costs were adjusted to 2009 and presented in US dollars. State-specific utility estimates were derived from patient-level European Quality of Life-5 Dimensions (EQ-5D) data from the VISTA RCT.26 Cost and health outcomes were discounted at 3%. The discounted QALY was 2.99 for VMP, 2.09 for MP and 2.95 for MPT. The total costs were US$110,870 for VMP, US$57,864 for MP and US$129,902 for MPT. The ICER of VMP versus MP was US$56,109 per QALY gained. VMP was dominant compared with MPT (greater benefit and lower cost). One-way sensitivity analyses were reported to show that the ICERs were robust, with the key drivers being the HR for VMP versus MP for the transition between second-line treatment and the HRs for MPT versus MP for treatment discontinuation. The authors concluded that VMP is cost-effective compared with MP in the USA.

Summary

The systematic review of cost-effectiveness showed that there were no fully published economic evaluations assessing the use of either bortezomib or thalidomide in combination with an alkylating agent and a corticosteroid as first-line treatment for people with MM who are ineligible for HDT. Five economic evaluations published as abstracts only were identified.7276 Of these evaluations, three compared MPT with MP72,74,75 and two compared VMP with MPT and MP.73,76 All three studies showed additional benefits from MPT compared with MP at additional cost, with cost per QALY gained ranging from £17,002 to £17,84772,74 in the UK and being AUS$20,998 in Australia.75 The two economic evaluations assessing VMP, MPT and MP showed that additional benefits were provided by VMP compared with MPT and by VMP and MPT compared with MP. The studies showed ICERs ranging from CAN$48,29473 to US$56,10976 per QALY gained for VMP compared with MP and CAN$31,975 per QALY gained73 and dominance76 for VMP compared with MPT. All of the studies had the involvement of the manufacturer of the interventions.

Systematic review of health-related quality-of-life studies

A systematic review was undertaken to assess the HRQoL of people suffering from and/or treated for MM. The aim was to provide data to populate the lifetime economic model with utilities to calculate QALYs. Although the methods used, and the process for their application, were similar to those described in Chapter 3 and Appendix 1, there were some variations. The selection criteria used to assess the titles and abstracts of studies and the full papers of those retrieved were modified. Although the primary focus of the review was on people with previously untreated MM who were not candidates for HDT with SCT, it was thought that there would be limited HRQoL data available. As a consequence, the selection criteria were broadened. Studies were included if they assessed the HRQoL of people with previously untreated MM who were not candidates for HDT with SCT using either a generic preference-based utility measure (e.g. the EQ-5D) or the EORTC QLQ-C30 disease-specific measure. Although the EORTC QLQ-C30 is a disease-specific measure rather than a generic preference-based measure, it is commonly used to assess HRQoL in cancer and mapping studies are available to convert this measure to other HRQoL utility values (i.e. EQ-5D). In addition, studies were included if they assessed the HRQoL of people with MM irrespective of treatments received as long as a generic preference-based measure was used.

Generic preference-based methods generate a HRQoL score using a choice-based method, such as time trade-off or standard gamble, which values patients' HRQoL on a scale between 0 (death) and 1 (perfect health).77 These measures use a generic questionnaire that can be used for most health conditions or diseases. The EQ-5D is the preferred measure of HRQoL in adults by NICE78 and has been used and validated in many different patient populations. The EQ-5D consists of five dimensions of health: mobility, self-care, ability to undertake usual activities, pain and discomfort, and anxiety and depression. HRQoL utility values are generated for patients' responses using an algorithm derived from a large UK population study.

The search strategy identified 208 papers that were potentially relevant. The titles and abstracts were screened with the full text of 18 papers retrieved for further inspection. After checking the retrieved papers, six studies met the inclusion criteria: five full papers and one abstract. A summary of the selection process and the reasons for exclusion are presented in Figure 6 and a list of excluded studies in Appendix 9. The 12 studies were excluded owing to the use of an inappropriate measure of QoL,7987 assessment of different population groups,80,82 or insufficient details due to publication as an abstract only.8890 The six studies included in the systematic review are summarised in Table 24. No generic preference-based QoL studies were found for newly diagnosed and untreated patients who were ineligible for HDT. Three studies focused on newly diagnosed and untreated patients; however, they were assessed either on the EORTC QLQ-C30 non-generic preference-based measure91,92 and/or received treatment not included in the current evaluation.92,93

FIGURE 6. Flow chart of identification of studies for inclusion in the review of QoL studies.

FIGURE 6

Flow chart of identification of studies for inclusion in the review of QoL studies.

TABLE 24. Characteristics of included QoL studies.

TABLE 24

Characteristics of included QoL studies.

Generic preference-based measures of HRQoL (i.e. EQ-5D) were assessed in four studies.9396 These four studies evaluated the EQ-5D among people with MM who were receiving either second-line or subsequent treatment,94,96 where treatment status was unclear95 or who had received or were receiving treatment not included in this evaluation.93,95,96 Two studies reported HRQoL for patients receiving interventions included in this evaluation,91,94 using the EORTC QLQ-C30 to assess patients newly diagnosed with MM receiving MP91 and patients with relapsed and refractory MM receiving bortezomib.94 The remainder of this section examines the six studies in more detail, providing an indication of the HRQoL of people with MM at different stages during their treatment.

Uyl-de Groot and colleagues96 investigated the HRQoL of patients with newly diagnosed MM who were treated in a tandem transplantation programme. All patients were scheduled for intensive treatment with vincristine, adriamycin and dexamethasone/vincristine, adriamycin and methyl prednisone (VAD/VAMP) chemotherapy followed by high-dose melphalan (HDM) and transplantation of whole blood stem cells and, finally, re-infusion of the previously collected peripheral stem cells. The EQ-5D questionnaire was completed, at several time points, by 51 patients with a mean age of 53 years. Table 25 shows the EQ-5D utility estimates at different time points. The utility estimates vary between 0.38 and 0.69, with the lower utility estimates during treatment periods or immediately after discharge of treatment. The longer term QoL estimates after discharge of treatment range from 0.64 to 0.69.

TABLE 25. European Quality of Life-5 Dimensions utility estimates for MM patients from Uyl-de Groot and colleagues.

TABLE 25

European Quality of Life-5 Dimensions utility estimates for MM patients from Uyl-de Groot and colleagues.

Slovacek and colleagues95 analysed the effect of selected demographics, and psychosocial and health aspects on HRQoL in MM survivors treated with HDT (melphalan) followed by autologous peripheral blood progenitor cell transplantation (PBPCT). Thirty-two patients of a mean age of 60 years completed the EQ-5D questionnaire. The EQ-5D estimate was 0.689.

Mujica-Mota and colleagues94 mapped HRQoL measurements from EORTC QLQ-C30 estimates to the EQ-5D utility measure for patients with relapsed and refractory MM from the SUMMIT-1 trial. Few details are given in this abstract. The authors stated that the utility scores appear similar across patient groups as defined by serological response to bortezomib, with an overall utility score of 0.65.

Van Agthoven and colleagues93 estimated the cost–utility of intensive chemotherapy versus intensive chemotherapy followed by myeloablative chemotherapy with autologous stem cell rescue in newly diagnosed and untreated patients with MM. There were 129 patients in the intensive chemotherapy arm and 132 in the myeloablative arm and all were less than 65 years old. Little detail was given on the methodology or results. The authors state that patients in an undefined state following intentionally curative primary therapy would have HRQoL 19.5% lower than those in the general population, i.e. 0.644.

Strasser-Weippl and colleagues92 evaluated baseline HRQoL in elderly patients recently diagnosed with MM who were previously untreated. Ninety-two patients (of median age 66 years) participated in the HRQoL substudy of an RCT of continuous or intermittent prednisolone plus vincristine, melphalan, cyclophosphamide, prednisolone, interferon-α-2b (VMCP-IFN-α-2b) for induction therapy. They used the EORTC QLQ-C30 questionnaire for these patients and compared them with a reference population for the general population of same age and gender (see Appendix 10 for observed scores). The study found a significant impairment of physical and psychosocial dimensions of QoL in patients with MM at baseline compared with a healthy reference population. Low psychosocial QoL at baseline was associated with poor prognosis.

Gullbrandsen and colleagues91 compared HRQoL scores of MM patients at diagnosis and over time with the scores of a reference population. Patients from two prospective Nordic Myeloma Study Group trials for HDM with autologous blood stem cell support (ABSCS) and MP completed the EORTC QLQ-C30 questionnaire. There were 221 patients for HDM who were < 60 years old and 203 patients for MP who were > 60 years old. The reference population consisted of 3000 randomly selected adults from the Norwegian population (see Appendix 10). At diagnosis, the most distressing problems were pain and fatigue, reduced physical functioning, limitations in role functioning and reduced overall HRQoL. These differences from the reference population were statistically significant, and large or moderate according to the rating systems. After the start of treatment, small to moderate improvements in mean QoL scores were observed for most domains.

Summary and conclusions of the health-related quality-of-life review

The systematic review did not find any generic preference-based HRQoL studies that were directly related to the population of interest. The utility estimates from HRQoL studies in patients with MM who had intensive therapy vary between 0.38 and 0.69, with the lower utility estimates during treatment periods or immediately after discharge from treatment.96 The longer-term HRQoL estimates after discharge from treatment range from 0.64 to 0.69. This may indicate that HRQoL is lower during the treatment period and improves after treatment has finished. Furthermore, long term HRQoL may be stable over time. It is unclear whether patients with CR following treatment have a higher HRQoL than those with other responses.

Review of the Janssen–Cilag submission to NICE (bortezomib)

A structured data extraction form was used to guide the review of the Janssen–Cilag submission to NICE (see Appendix 11). The MS reports the total costs, the QALYs gained and the cost-effectiveness associated with the interventions under consideration in the appraisal. The model evaluates lifetime costs and benefits for bortezomib in combination with MP (VMP), for previously untreated MM patients not eligible for HDT–SCT, compared with MPT, CTDa and MP. The perspective of the analysis is clearly stated as being that of the NHS and PSS, capturing direct costs and benefits only.

Modelling approach

A decision-analytic cost–utility model, developed in Microsoft Excel, was used in this submission. The model uses a cohort of newly diagnosed myeloma patients treated with MP as the baseline treatment. Treatment effects for VMP, MPT and CTDa are then modelled over time by adjusting the baseline patient experience via HRs. A survival model appears to be used, which estimates OS and PFS curves for each of the comparators. The model also includes further lines of treatment (second- and third-line) to estimate the total treatment costs.

The analytic framework was based on a variant of Quality-Adjusted Analysis of Time Without Symptoms or Toxicity (Q-TWiST97) using partitioned survival analysis, and utilises the area under, and the difference between, time-to-event curves to estimate mean durations spent within the disease states of interest.

Survival is partitioned into three different states: (1) prior to response to treatment; (2) response but no progression; and (3) post progression. Death represents the final state. The time to response or death was estimated from life tables constructed directly from the VISTA trial patient-level data.26 PFS for MP was estimated from a meta-analysis of the MP arms of included RCTs to compute MP PFS values at 6, 12, 18 and 24 months. PFS was extrapolated beyond 24 months, assuming an exponential survival distribution, using the hazard rate for all time periods beyond 24 months equal to the hazard rate calculated between months 18 and 24. OS for MP was estimated in a similar way to PFS, but using 48 months of summary survival data from the MP arms of the included RCTs.

For the comparator treatments, relative HRs were taken from the random effects results of the meta-analysis that used OS and PFS summary data. OS and PFS hazard rates were computed for each time period by multiplying the VMP–MP, MPT–MP and CTDa–MP HRs by the appropriate hazard rate for that time period. The computed hazard rates were then used to generate the VMP, MPT and CTDa OS and PFS life tables that extend out to the end of the 30-year lifetime horizon of the model.

The HRs were estimated using a piece-wise constant hazard model using derived survival data from the Kaplan–Meier curves for each of the included RCTs. HRs were estimated at 48 months for OS for each of the RCTs, except the VISTA Trial, which had only 36 months' follow-up. For estimation of the OS hazard for thalidomide, data from five RCTs were used, which included RCTs that had included thalidomide maintenance. Data were synthesised using Bayesian meta-analysis with fixed and/or random effects models. Results from the random effects model were used in the cost-effectiveness model. (AiC/CiC information has been removed.)

Following the first-line therapy, and upon disease progression, it was assumed that the second-line treatment would consist of bortezomib plus high-dose dexamethasone (HDD), CTDa or HDD. Most patients received CTDa after first-line VMP and bortezomib and HDD for all other first-line therapies. All patients received lenalidomide plus dexamethasone as third-line treatment.

Adverse events were included in the analysis by estimating the incidence of AEs (grades 3 and 4) across the RCTs for each of the comparators and combining this with the unit costs of treating the AEs. Unit costs were mostly based upon those used in a previous NICE report for lenalidomide (TA171).31 The most common AEs for MPT were non-haematological toxicity, neutropenia and deep venous thrombosis; for MP they were neutropenia, anaemia and thrombocytopenia; and for VMP they were neutropenia, oedema, leucopenia and thrombocytopenia.

Assumptions

The manufacturer's model makes the following assumptions:

  • Dose of thalidomide of 150 mg per day for MPT and 167 mg per day for CTDa.
  • Adverse events are included in the model as the cost of treating them; the incidence of AEs does not influence the treatment duration, efficacy or patient utility.
  • Costs included for second- and third-line treatments. Most patients who received VMP as first-line treatment receive CTDa as second-line treatment and most who did not receive VMP as first-line treatment do receive it as second-line treatment.
  • Thalidomide RCTs that included maintenance therapy with thalidomide were included in the meta-analysis.

Appraisal of the manufacturer's cost-effectiveness analysis

The Janssen–Cilag MS was appraised for methodological quality and generalisability to the UK NHS using a checklist adapted from the NICE reference case requirements78 and the Philips and colleagues checklist (see Appendix 12).98 The submission meets all of the requirements for methodological quality and generalisability, except that it did not provide any evidence that the economic model had been validated.

The evaluation provided a clear statement of the decision problem to be addressed, including the population, which appeared to follow the scope for the appraisal issued by NICE. The comparators included (VMP, CTDa, MP and MPT) were appropriate as these are being routinely used or considered for use within the NHS in England and Wales. The perspective for the model was the NHS and PSS. A survival modelling methodology was used which seemed appropriate given the clinical nature of MM. The lifetime horizon used in the model reflects NICE guidance. The model structure was clearly presented with a description and justification of the key assumptions and data inputs used. Measures of clinical effectiveness are from a systematic review of RCTs with an MTC. Benefits for the model are measured in QALYs using the EQ-5D for measuring utility. All benefits and costs are discounted at 3.5% as outlined in NICE guidance.78 Data on PPS were extrapolated from observed data using an exponential distribution. Uncertainty was assessed through a one-way deterministic sensitivity analysis and probabilistic sensitivity analysis (PSA). It was unclear if the model had been fully validated, as no details were provided.

Estimation of quality-adjusted life-years

Health-related quality of life utility values are assigned to each of the states: prior to response to treatment, response to treatment without progression, and post progression, based on a study evaluating chemotherapy followed by SCT in people with MM.93 For the response state, a utility value of 0.81 was used, based on the utility of the general public at an age (median 54 years) corresponding to that of the patients in the study. A utility value of 0.64 was applied to the post-progression disease state. A utility value of 0.77 was applied to patients prior to the response to treatment. The submission considered this the most appropriate source of utility values because it is the only study that reports utility values according to response and progression status and, secondly, utility values were derived using the EQ-5D rather than the less methodologically robust indirect mapping approaches used in the other studies. However, as shown in the systematic review of HRQoL, there are several other more relevant HRQoL studies. In particular, it is unlikely that patients with MM would have the same HRQoL as the general population.

Estimation of costs

Treatment unit costs and doses were based on the British National Formulary (BNF) No. 5735 and MIMS 2009.99 The duration of treatment was based upon the mean treatment duration in the trials and was assumed to incorporate discontinuation of treatment due to progression, death and AEs. The duration of treatment with MP was seven cycles as per the VISTA trial.26

For bortezomib, (AiC/CiC information has been removed) vials were used per patient (VISTA trial26); the reason why the number of vials used is far fewer than the full treatment course of 52 vials is not given. The submission used an average dose of 150 mg per day for thalidomide obtained from the five MPT RCTs included in the meta-analysis of the MS. Within the CTDa combination, a daily dose of 167 mg was used for thalidomide. This is the weighted average as per protocol escalating dose from the MMIX RCT prior to the maintenance phase. A mean duration of treatment with thalidomide of 315 days was used, based on the duration reported in the MPT RCTs.

The resource use cost for the management of first-line MM was assumed to be the same for patients receiving VMP, MPT, CTDa and MP. There was an outpatient cost of £102 per visit and a total of nine outpatient visits. In addition, patients receiving VMP had this outpatient cost each time they were administered bortezomib.

Cost-effectiveness results

Table 26 shows the base-case results from the submission. The ICER for VMP versus MP is estimated to be £10,498. Furthermore the ICERs of VMP versus MPT and VMP versus CTDa are estimated to be £11,907 and £10,411, respectively. The submission states that the incremental analysis shows extended dominance of MTP over CTDa. However, the assessment group has found an error in the calculation of third-line costs for CTDa (correct cost £24,978 instead of £16,652). Correction of this error resulted in an ICER of £51,552 per QALY gained for CTDa versus MP.

TABLE 26. Base-case results for the Janssen–Cilag submission.

TABLE 26

Base-case results for the Janssen–Cilag submission.

One-way sensitivity analyses were undertaken for a limited number of parameters, including different survival distributions for OS and PFS, alternative HRs for OS, dose and duration of thalidomide, utilities, time horizon and discounting rate. The results are generally robust to changes in the sensitivity analyses. The model is most sensitive to the following parameters: underlying MP survival hazard, HRs for OS, dose of thalidomide, and duration of treatment with thalidomide in the MPT arm.

A PSA was undertaken using Monte Carlo simulation with 10,000 iterations. All parameters in the model were included except medication costs. For the PSA, at the £20,000 and £30,000 willingness to pay thresholds, VMP has the highest probability of being cost-effective: 64% and 75%, respectively.

Two scenario analyses were conducted. Scenario A did not include the costs of subsequent therapy after first-line treatment. In this scenario, the cost-effectiveness results were less favourable for each of the treatments and the ICERs increase to £48,437, £16,956 and £21,099 per QALY gained for CTDa, MPT and VMP compared with MP, respectively. Scenario B assumed the same second-line therapies as those treated with MP in the VISTA26 RCT. The results were similar for this scenario to the base-case analyses.

Summary of general concerns

  • Hazard ratio used for OS for thalidomide was derived from a meta-analysis that included RCTs with thalidomide maintenance.
  • The utility estimates were from a study with the wrong population, i.e. younger patients who received high-dose therapy. Furthermore, patients who had responded to treatment were assumed to have the same utility as the general population.
  • There was an error in the calculation of third-line costs for CTDa.
  • There was no evidence provided of model validation.

Review of the Celgene submission to NICE (thalidomide)

Overview

A structured data extraction form was used to guide the review of the Celgene submission to NICE (see Appendix 11). The submission states that its objective is to provide an evaluation comparing the costs and benefits of MPT with those of VMP and MP in patients with MM who are older than 65 years or who are ineligible to receive HDT. The evaluation has two stages. First, a short unsystematic review examines the literature for any relevant cost-effectiveness models in general and specifically in previously untreated MM patients who are not eligible for HDT. The review of cost-effectiveness studies indicates that a literature search was undertaken, although no details of the search strategy or methods for the review are provided. Searches identified five publications, with only one having relevance to the scope of the appraisal. The study by Deniz and colleagues72 compared MPT with MP as first-line treatment for MM in Scotland and provided the basis for the model developed for the submission by Celgene. Second, an economic model has been developed using data on the clinical effectiveness of MPT23,59 and VMP26 through a Bayesian MTC. The perspective of the economic evaluation is stated as being that of the NHS and PSS, including direct costs and benefits only. The analysis takes a lifetime horizon (30 years), presenting costs and outcomes (i.e. years of life gained and QALYs gained) for the three treatment arms of MPT, MP and VMP and an incremental analysis of costs and outcomes for MP and VMP when compared with MPT.

Modelling approach

A Markov model was developed to compare the difference in the progression of MM and in the costs of treatment when managed with the three different treatment options of MPT, VMP or MP through a series of different health states. It was developed from a model produced by Deniz and colleagues,72 which compared MPT and MP as first-line treatment for MM in Scotland.

The model has four different health states that are defined by the stage of disease progression or the occurrence of AEs. The four states are preprogression without AEs, preprogression with AEs, post progression and an absorbing state of death. All patients start in the preprogression without AEs state and move to other states if their condition worsens or they incur an AE. As MM is a progressive condition, people can only move to a worse state or remain in the same state. The submission provides limited discussion of the rationale for the approach or of the basis for the transition probabilities used to determine progression between states and other approaches assessing the phases of treatment may reflect variations in HRQoL more closely.

The model has a cycle length of 6 weeks (42 days) with a maximum of 12 cycles for MPT and MP and nine cycles for VMP. The cycle length and the number of cycles correspond to those used in clinical RCTs.23,26,59 The time horizon used in the model equates to a lifetime horizon, although characteristics of the cohort used in the model are not clearly stated. The consequences of a shorter time horizon of 5 years were examined in the sensitivity analysis.

Treatment effects were calculated from a random effects Bayesian MTC of data originating from three RCTs.23,26,59 The MTC was undertaken despite differences in the dosage used in the RCTs comparing MP with MPT. It used measures of survival time before and after progression as the primary outcomes. TTP and PFS were used and assumed to be equivalent. The outcome from the MTC was a measure of the risk of progression, provided through the percentage of patients experiencing PFS at 6-month intervals up to 30 months, with extrapolation beyond this point using an exponential distribution. It was assumed that post-progression survival (PPS) would be the same irrespective of preprogression treatment, with the different arms assumed to receive the same alternative treatment after progression (i.e. second- and third-line treatments). PPS was calculated by combining the MPT, MP and MEL100 (VAD, cyclophosphamide and melphalan 100 mg/m2) arms from the IFM 99/06 trial to create an average survival curve.23 Average survival at different time points was then extrapolated with an exponential distribution. Treatment interruptions or discontinuations were encompassed in the trial efficacy data for MP and MPT, with no alteration to costs in the base case. Changes in cost were encompassed in sensitivity analyses through a reduction in dose as they are likely to reflect clinical practice. No data were available for VMP on discontinuation.

Adverse events were included for people on active treatment only if they were treatment related and considered to be clinically significant (i.e. grade 3 or above or occurred in 2% or more of patients in either arm). Those associated with disease progression were not incorporated into the model. The treatment-related AEs were included in the model through an estimate of the risk of AEs per cycle based on trial data.23,26 The effects of AEs on HRQoL were also included in the model. A literature search revealed no HRQoL data specific to MM, and so HRQoL decrements were obtained for different patient populations. Costs of AEs were also included.

Assumptions

The manufacturer's model makes the following additional assumptions:

  • Post-progression survival is modelled to be the same across different treatment strategies.
  • Patients assumed to discontinue first-line treatment upon disease progression.
  • Deaths can only occur at or after progression and are assumed to be due to disease-related deterioration.
  • Adverse events are included in the model as a utility decrement at the time of the event and the cost of treating them. They are assumed to not affect the disease progression rate or OS, or treatment duration, efficacy or dose.
  • Assumes venous thromboembolism (VTE) antithrombotic prophylaxis for 5 months for patients receiving MPT with no resultant risk in incidence of VTEs, and antiviral prophylaxis for VMP.

Appraisal of the manufacturer's cost-effectiveness analysis

The Celgene MS was appraised for methodological quality and generalisability to the UK NHS using a checklist adapted from the NICE reference case requirements78 and the Philips and colleagues checklist (see Appendix 12).98 Although the economic evaluation lacked detail on some criteria, it adhered to the scope of the appraisal and followed the many aspects of the NICE reference case.

The evaluation provided a clear statement of the decision problem to be addressed, which appeared to follow the scope for the appraisal issued by NICE. Despite stating that the model focused on first-line therapy for people with MM who are ineligible for HDT and/or are aged over 65 years, insufficient details were provided of the population cohort used in the model itself. The comparisons of MP, MPT and VMP were appropriate as these are being routinely used or considered for use within the NHS in England and Wales. The setting for the evaluation was England and Wales and the perspective for the model was that of the NHS and PSS. A Markov modelling methodology was used which was developed from a previous evaluation.72 The methodology seemed appropriate given the progressive nature of MM through distinct stages. The lifetime horizon (30 years) used in the model reflects NICE guidance.

Although the model structure was presented, limited details are given linking the model structure to the baseline risk of the condition. The submission outlines and justifies the assumptions used in the model and the different benefit, resource and cost inputs and their sources. Measures of clinical effectiveness are from a systematic review of RCTs with an MTC. Benefits for the model are measured in QALYs using the EQ-5D for measuring utility. All benefits and costs are discounted at 3.5%, as outlined in NICE guidance.78 Data on PPS were extrapolated from observed data using an exponential distribution. While uncertainty has been assessed through a one-way deterministic sensitivity analysis, no probabilistic analysis or model validation processes were undertaken. As a consequence, the analysis provides only a partial assessment of the uncertainty in the model with the possibility of correlation between parameters and difficulty in summarising the implications of uncertainty.

Estimation of quality-adjusted life-years

No systematic review was undertaken to identify HRQoL values associated with the benefits of the treatment, but a literature search was conducted to identify utility decrements for AEs. The HOVON 24 study,93 an RCT of intensive chemotherapy followed by myeloblative therapy with autologous stem cell rescue compared with intensive chemotherapy, provided HRQoL data using the EQ-5D to assess the benefits of treatment for people with MM. Although not directly relevant in terms of the population and treatments included in the scope for the technology appraisal, it does provide an indication of the possible utilities for managing people with MM when specific assumptions are applied. The utility values used were 0.64 for people not responding to treatment and 0.81 for people who did respond (using general public utility for same age group). A utility value of 0.77 at 24 months was used for those who continue to respond to treatment with intensive chemotherapy and had not progressed. An assumption was made that preprogression patients and post-progression patients matched responders and non-responders in the HOVON trial.93 However, other more relevant HRQoL studies (see Systematic review of health-related quality-of-life studies, above) show that the utility values used in the MS are higher than would be experienced by people with MM, whether newly diagnosed (0.52), undergoing treatment (0.38–0.55) or after treatment at 6 months (0.64) and 12 months (0.69).

The literature search for utility decrements for AEs did not identify specific values for people with MM and so utility values from different population groups were used (e.g. breast, colon and rectal cancer). Average per cent reduction in utility by each AE was calculated from these values and applied to the cohort in the model.

Estimation of costs

Resources and costs were obtained from several sources. NHS resources were from an unpublished survey of UK haematologists by Celgene Ltd. Inpatient, outpatient and day-case hospitalisation costs were derived from NHS Reference Costs,100 including inpatient and day-care costs for disease-related complications and treatment-related AEs, outpatient consultations and disease monitoring tests and treatment care costs in primary care. Costs of medicines were from the BNF (No. 57)35 and costs of blood transfusions from Wilson and colleagues101 with costs inflated to 2008.102 When on active treatment, patients receive the mean observed treatment dose from the trials. Other resource use and cost data were provided for outpatient consultations, disease monitoring and treatment of AEs/complications. No indirect costs were included in the model. The costs of AEs were calculated by combining resource use data from the survey of haematologists with unit costs to estimate total costs. These costs and trial data on the frequency of AEs23 were then used to calculate a weighted average cycle cost. The methods for deriving resources and costs used and the sources were clearly described.

Cost-effectiveness results

The submission reports the benefits [i.e. TTP, patients progressed, deaths, proportion of patients with AEs, median OS, mean survival in years of life (life-years) and total QALYs] and the total costs (i.e. medication, monitoring and management of AEs) separately for each treatment pathway in the model.

Comparison of the benefits used for the model showed considerable benefit for those receiving MPT or VMP over MP on median TTP, median OS, total life-years and total QALYs. In contrast, more people receiving MPT (43.2%) or VMP (40.9%) suffered AEs compared with those receiving MP (13.4%). The total costs of the different treatment strategies used within the model showed considerable variation between MP (£1365) and VMP (£42,616). The cost of the medications was the main reason for these differences.

The base-case analyses (Table 27) produced two comparisons, MPT versus MP and VMP versus MPT, with differing outcomes. When compared with MP, MPT had an ICER of £18,188 per life-year gained and £23,381 per QALY gained. In contrast, the comparison of VMP with MPT showed that VMP produced a small benefit in additional life-years and QALYs at a large additional cost (£21,483). The resultant ICERs were £200,237 per life-year gained and £303,845 per QALY gained.

TABLE 27. Base-case results for the Celgene submission.

TABLE 27

Base-case results for the Celgene submission.

The submission assessed uncertainty through one-way deterministic sensitivity analyses. No PSA was conducted as the manufacturer stated that the efficacy of MPT and VMP were essentially the same and that the cost differences would be the key driver for the model. The submission included a number of one-way sensitivity analyses for parameter values and model structure. The parameters with the greatest effect on the model results were for the changes in treatment efficacy with a range of £16,586–33,275 per QALY gained for MPT versus MP and a range of £148,873–1,000,435 per QALY gained for VMP versus MPT.

The submission concludes that MPT represents a cost-effective use of NHS resources compared with MP as a first-line therapy for people with MM who are not eligible for HDT and/or are aged over 65 years. In contrast, when comparing MPT and VMP the manufacturer stated there was negligible clinical benefit from VMP at an additional cost that resulted in the ICERs exceeding £300,000 per QALY. When these findings were assessed through sensitivity analysis, the ICERs were reasonably robust.

Summary of general concerns

  • The economic evaluation focuses on the effectiveness of first-line treatment for people with MM who were ineligible for HDT, reflecting the scope for the NICE technology appraisal. Exclusion of second- or third-line treatment options may oversimplify the evaluation with consequences for the incremental benefits and costs that would result from different possible options available. Given that first-line treatment may, in part, determine subsequent treatment options, it would be helpful to include these in the evaluation.
  • All deaths are assumed to be caused by disease-related deterioration and occur only at or after progression. In practice, deaths may and do occur prior to progression and, as such, the evaluation may overestimate the benefits that are accrued.
  • Post-progression survival was the same irrespective of preprogression treatment, which would affect the incremental benefits.
  • No HRQoL studies relevant to the evaluation were identified by the manufacturer and utility values from comparisons of different MM populations using alternative management strategies were used.

Comparison of manufacturers' results

The manufacturers' economic models had similar structures but used different methodology: one used a survival model and the other a Markov model. Both models compared first-line treatment with VMP, MPT and MP. Janssen–Cilag also included CTDa as a comparator. The ICERs produced by the Janssen–Cilag and Celgene submissions vary considerably from £11,907 to £303,845 per QALY gained for VMP versus MPT. These differences stem from the number of vials used for treatment with bortezomib, the HRs for thalidomide and the inclusion of second- and third-line treatments.

SHTAC independent economic assessment

Overview

We developed a new model to estimate the costs, benefits and cost-effectiveness of MPT, VMP and CTDa compared with MP, in newly diagnosed patients with MM ineligible for HDT–SCT. CTDa was included in order to compare all relevant comparators; however, there are limitations to the effectiveness data, as the effectiveness estimate for OS was not statistically significant and the MMIX RCT included a second randomisation to thalidomide maintenance for some patients. The model was populated with clinical effectiveness data from the included RCTs in our systematic review of effectiveness (Chapter 4), HRQoL data from a systematic review of HRQoL studies (see Systematic review of health-related quality-of-life studies) and cost data derived from published studies (where available) and from national and local NHS unit costs.

The economic evaluation was from the perspective of the NHS and PSS, as only these direct costs were included. The model estimates the lifelong costs and benefits from each of the treatments. The costs and benefits were discounted at 3.5%, as recommended by NICE.78 The base-price year for the costs was 2009. The intervention effect in terms of improvement in OS and PFS was derived from the systematic review of effectiveness reported in Chapter 4 (see Overall survival and Progression-free survival). The outcome of the economic evaluation is reported as cost per QALY gained.

Description of the SHTAC model

A survival model was used to compare the cost-effectiveness estimates of VMP, CTDa and MPT versus MP. The model uses a survival analysis approach to estimate the mean OS and PFS for each of the interventions for a cohort of patients with newly diagnosed MM. The model consisted of cycles of 6 weeks in length to be consistent with the cycle lengths used for chemotherapy treatment. A lifetime horizon of 30 years was modelled to capture all clinical events using partitioned survival analysis for OS and PFS. Two survival curves were constructed for OS and PFS (Figure 7b), based on the derived probability of death and progression in each model cycle, respectively. The mean time spent in each state was calculated from the survival curves for OS and PFS (see Figure 7a).

FIGURE 7. The survival model adopted for the cost-effectiveness model.

FIGURE 7

The survival model adopted for the cost-effectiveness model. Treatment and post-treatment health states refer to first-line treatment.

Survival was classified into three health states, and the mean time spent in each state is as follows:

  • Treatment (Ttreat) is the mean duration of first-line treatment.
  • Post treatment (TPost_treat) is the mean time from stopping first-line treatment until progression, i.e. TPFSTtreat
  • Post progression (Tprog) is the time from disease progression until death, i.e. TOSTPFS, where TOS is mean OS and TPFS is mean PFS.

Each health state was associated with a HRQoL utility estimate that was multiplied by the length of time spent in that state. The total QALYs over the lifetime of a patient were calculated by aggregating the estimated QALYs from each health state.

Due to lack of data on subsequent therapies, it was unclear how the subsequent therapies affected HRQoL and survival and therefore second-line therapy is only included in the model as a cost.

The methodology used for deriving the parameters for the survival curves for the alternative treatments is as follows:

  1. Construct the baseline survival curves for MP using the adjusted event probability for each time interval.
  2. Construct the survival curves for other treatments by using the event probability for each time interval; i.e. event probability for MP multiplied by HR for treatment option.

For the baseline MP treatment, OS and PFS at regular time points were derived for each of the included studies from our meta-analysis of the clinical RCTs. The data from the RCTs were combined to form baseline MP OS and PFS curves. These curves provided the probability of an event (death or disease progression), i.e. hazard rate, for MP in each time interval (see Baseline MP curves).

The treatment effects for the other interventions compared with MP (HRs) were taken from our systematic review of clinical effectiveness (see Assessment of effectiveness). As the HR of the treatments versus MP varied over time, a constant HR was not appropriate. We estimated the HR for each 6-monthly period for each of the treatments versus MP.

The hazard rate for death was derived for each of the treatments by multiplying the baseline MP probability of death by the HRs for each time interval. The hazard rate for disease progression was derived in a similar manner. This method provided a closer fit to the trial data than approximations, such as fitting distributions. Parameters used in the model and the data sources used to derive them are described in more detail below (see SHTAC data sources). The methodology used for deriving the survival curves is described in more detail in Appendix 13.

The costs in the model comprise drug treatment, consultation, monitoring costs, and costs for treating AEs. Patients remained on drug treatment unless their disease progressed or they died. All patients who had not died received second-line therapy and this was assumed to start at the mean time of disease progression for the cohort. Third-line therapy was not included as it was assumed that most patients would receive lenalidomide, irrespective of the initial treatment. Costs used in the model are described in more detail below (see Estimation of costs).

A list of the model assumptions is given below. Assumptions are applied to all treatment options unless explicitly stated otherwise. All assumptions were tested in sensitivity analyses.

The model includes the following assumptions:

  • For bortezomib, each patient receives one vial per administration.
  • Costs included for second-line treatments. Most patients who received VMP as first-line treatment receive CTDa as second-line treatment and most who did not receive bortezomib as first-line treatment receive it as second-line treatment.
  • Costs and outcomes of third-line and subsequent treatments are assumed to be the same between arms.
  • Patients discontinue first-line treatment upon disease progression.
  • Health-related quality of life is better for those with CR than those with less than CR and is assumed to improve when patients stop treatment.
  • AEs are not modelled explicitly in the model for patient outcomes, i.e. OS and PFS, but are included as additional cost for treating the AEs in the model.

In each cycle the total costs and QALYs are calculated by multiplying the individual costs and HRQoL by the number of people in the cohort still alive for each of the treatments. The total lifetime costs and QALYs are calculated by aggregating the costs and QALYs for all cycles. The total discounted QALY gain and cost of treatments are calculated. Thus, the cost-effectiveness of each of the treatments is calculated,

Cost-effectiveness=Cost for treatmentCost for MP treatmentQALYs for treatmentQALYs for MP treatment
[Equation 1]

Evaluation of uncertainty

The evaluation of the cost-effectiveness of treatment for MM is based on uncertain information about variables, such as the clinical effect, HRQoL and resource use. This uncertainty was evaluated using deterministic and probabilistic sensitivity analyses. One-way deterministic sensitivity analyses were conducted to evaluate the influence of individual parameters on the model results and test the robustness of the cost-effectiveness results to variations in the structural assumptions and parameter inputs (see Deterministic sensitivity analysis, below).

Multiparameter uncertainty in the model was addressed using PSA (see Probabilistic sensitivity analysis, below).103 In the PSA, probability distributions are assigned to the point estimates used in the base-case analysis. The model is run for 1000 iterations, with a different set of parameter values for each iteration, by sampling parameter values at random from their probability distributions. The uncertainty surrounding the cost-effectiveness of the treatment is represented on a cost-effectiveness acceptability curve (CEAC) according to the probability that the intervention will be cost-effective at a particular willingness-to-pay threshold. Appendix 14 reports the parameters included in the PSA, the form of distribution used for sampling each parameter, and the upper and lower limits assumed for each variable.

Model validation

The SHTAC model was validated by checking the model structure, calculations and data inputs for technical correctness. The structure was reviewed by clinical experts for appropriateness for the disease and its treatment. The SHTAC model was checked for internal consistency against the MS economic models by running the SHTAC model with the inputs used in MS models to ensure similar results. The robustness of the model to changes in input values was tested using sensitivity analyses to ensure that any changes to the input values produced changes to the results of the expected direction and magnitude. Finally, the model results were compared with those from the MSs.

SHTAC data sources

Baseline MP curves

The baseline MP OS curve was generated using the MP OS curves from the RCTs included in our systematic review of clinical effectiveness (see Chapter 4, Overall survival). Survival probabilities (at 6-month intervals) were extracted from a scanned copy of the Kaplan–Meier plots for each MP group using the digitising software Engauge104 (Appendix 13). A weighted average of the survival probabilities for each time point was calculated to provide a summary MP OS curve (Table 28 and Figure 8) using the number of participants in the trials as weights.

TABLE 28. Overall survival probabilities extracted from Kaplan–Meier plots for MP study arms using digitising software.

TABLE 28

Overall survival probabilities extracted from Kaplan–Meier plots for MP study arms using digitising software.

FIGURE 8. Summary curve for MP OS obtained from weighted average of individual MP curves.

FIGURE 8

Summary curve for MP OS obtained from weighted average of individual MP curves.

A baseline MP PFS curve was generated using the PFS curves from the trial data included in our systematic review of clinical effectiveness (see Chapter 4, Progression-free survival) in a similar way to the baseline OS curves – see Appendix 13 and Table 29. A weighted average of the PFS probabilities for each 6-month time point was calculated to provide a summary MP PFS curve (Figure 9) using of participants in the trials as weights.

TABLE 29. Progression-free survival probabilities extracted from Kaplan–Meier plots using digitising software.

TABLE 29

Progression-free survival probabilities extracted from Kaplan–Meier plots using digitising software.

FIGURE 9. Summary curve for PFS obtained from weighted average of individual PFS data in MP arms of trials.

FIGURE 9

Summary curve for PFS obtained from weighted average of individual PFS data in MP arms of trials.

The probability of an event at each time interval for the MP treatment arm (hazard OS and hazard PFS) is calculated from the baseline MP OS and MP PFS curves. These probabilities are shown in Table 30. The hazard rate for an event for MP per cycle is estimated for each time point, ti:

TABLE 30. Hazard rate for MP for OS and PFS (event rate per cycle).

TABLE 30

Hazard rate for MP for OS and PFS (event rate per cycle).

h(ti)=1(s(ti)s(ti1))1(titi1)
[Equation 2]

where s(t) is the survival function over time t.

For OS, few individuals were followed up for more than 36 months, and so a constant hazard rate was assumed after 36 months using the hazard rate in the first 36 months. For PFS, few individuals were followed up for more than 24 months, and so a constant hazard rate was assumed after 24 months using the hazard rate in the first 24 months. The methodology used to derive the survival curves is described in more detail in Appendix 13.

Overall survival and progression-free survival hazard ratios for treatments versus MP

The relative effectiveness of the treatments versus MP for OS and PFS were represented as HRs. The HRs were obtained from the Kaplan–Meier plots in the trial publications (see Overall survival and Progression-free survival). As the HR of the treatments versus MP varied over time, a constant HR was not appropriate. We derived the HR for each 6-monthly period for each of the treatments versus MP.

The HR for each treatmentj versus MP at each time point ti is,

HRi=hj(ti)hmp(ti)
[Equation 3]

The HRs for the MPT trials summary were combined using simple weighted averages of the proportion of surviving patients in each trial arm at each time point, weighted by numbers of patients in the trial. The HRs were assumed to be constant after 36 months for OS and 24 months for PFS as there were few patients with more than this length of follow-up in the trials. HRs of OS and PFS are shown in Tables 31 and 32, respectively.

TABLE 31. Hazard ratios for OS from trial publications and by derivation from publication Kaplan–Meier plots.

TABLE 31

Hazard ratios for OS from trial publications and by derivation from publication Kaplan–Meier plots.

TABLE 32. Hazard ratios for PFS from trial publications and by derivation from publication Kaplan–Meier plots.

TABLE 32

Hazard ratios for PFS from trial publications and by derivation from publication Kaplan–Meier plots.

The event rate at each time interval for MPT, VMP and CTDa was estimated by multiplying the risk of death or progression by the HR for each cycle. The effects of using alternative HRs were evaluated in sensitivity analyses. It should be noted that the MMIX RCT included a second randomisation to maintenance therapy with thalidomide for some patients after first-line therapy and there were no data available for OS and PFS for patients who did not have maintenance therapy.

Complete response

Complete response outcome data for each treatment option is described in Chapter 4 (see Response to treatment). For each treatment option, the relative risk of CR compared with MP was derived using Review Manager 5. The CR rate for MP was estimated using the trial data by simple weighted average of the MP arm using the number of trial participants as the weight. CR for the other treatment options was derived by multiplying the MP CR rate by the relative risk. Table 33 shows the CR data used in the model for MP, VMP, MPT and CTDa.

TABLE 33. Complete response for different treatment.

TABLE 33

Complete response for different treatment.

Health-related quality of life

Although our systematic review of HRQoL studies (see Systematic review of health-related quality-of-life studies) did not find any generic preference-based HRQoL studies of people with untreated MM who were not eligible for HDT with SCT, it did identify two studies that assessed HRQoL in this group using the EORTC QLQ-C30. A targeted search was therefore conducted for studies that mapped data from the EORTC QLQ-C30 onto the EQ-5D to enable the estimation of health state values based on EORTC QLQ-C30 data. The EORTC QLQ-C30 is the most commonly used instrument to measure the HRQoL of cancer patients. Two studies were identified.106,107

McKenzie and van der Pol107 used an ordinary least squares (OLS) regression analysis with data from an RCT of palliative therapies for 199 patients with inoperable oesophageal cancer, with an average age of 74.8 years. The regression results for the mapping are shown in Table 34.

TABLE 34. Regression results for mapping between EORTC QLQ-C30 and EQ-5D from McKenzie and van der Pol.

TABLE 34

Regression results for mapping between EORTC QLQ-C30 and EQ-5D from McKenzie and van der Pol.

Kontodimopoulos and colleagues106 used an OLS regression with data from 48 patients with gastric cancer, split into equal subgroups by age, sex and chemotherapy scheme. Three scales were significant predictors (p < 0.05 or better) of EQ-5D indices: physical functioning, emotional functioning and global health status. The regression results for the mapping are shown in Table 35.

TABLE 35. Regression results for mapping between EORTC QLQ-C30 and EQ-5D from Kontodimopoulos and colleagues.

TABLE 35

Regression results for mapping between EORTC QLQ-C30 and EQ-5D from Kontodimopoulos and colleagues.

Our systematic review of HRQoL studies found two studies in the population of interest but these used the EORTC QLQ-C30.91,92 For both studies, we mapped the EORTC QLQ-C30 HRQoL scores to the EQ-5D using each of the mapping algorithms described above (Tables 36 and 37).

TABLE 36. European Quality of Life-5 Dimensions utility values derived by mapping from EORTC QLQ-C30 HRQoL scores from Strasser-Weipl and Ludwig.

TABLE 36

European Quality of Life-5 Dimensions utility values derived by mapping from EORTC QLQ-C30 HRQoL scores from Strasser-Weipl and Ludwig.

TABLE 37. European Quality of Life-5 Dimensions utility values derived by mapping from EORTC QLQ-C30 HRQoL scores from Gulbrandsen et al.

TABLE 37

European Quality of Life-5 Dimensions utility values derived by mapping from EORTC QLQ-C30 HRQoL scores from Gulbrandsen et al.

Gulbrandsen and colleagues91 provide HRQoL at different time points. Based on this study, it appears that HRQoL is lower during the treatment period and improves after treatment has finished and this is consistent with HRQoL results from Uyl-de Groot and colleagues.96 Long-term HRQoL appears to be stable over time. In addition, the utility estimates from the HRQoL studies in populations treated with HDT are similar to those from Gulbrandsen and colleagues.91

The accuracy of the mapping studies was assessed for the study by Uyl-de Groot and colleagues,96 which reported EORTC QLQ-C30 and EQ-5D results. Figure 10 shows the comparison between the EQ-5D utility estimates using the two mapping methods compared with the EQ-5D data from Uyl-de Groot and colleagues. For these data, the mapping algorithm by McKenzie and van der Pol provides the better fit and for most time points is a good fit to the data.

FIGURE 10. Comparison of results from mapping studies from EORTC QLQ-C30 to EQ-5D with EQ-5D data from Uyl-de Groot and colleagues.

FIGURE 10

Comparison of results from mapping studies from EORTC QLQ-C30 to EQ-5D with EQ-5D data from Uyl-de Groot and colleagues.

We suggest that the most appropriate source of HRQoL data for the treatment period and post-treatment values is from Gulbrandsen and colleagues91 from the mapping by McKenzie and van der Pol. These utility estimates are shown in Table 37. The utility estimates for the treatment period are for the 1-month time point, i.e. 0.58, and for post treatment (and post progression) is an average of the 6- to 36-month time points, i.e. 0.68.

Complete response

Health-related quality-of-life data from the MMIX RCT57 were analysed to determine whether patients with CR had a better HRQoL after response than those with other levels of response. EORTC QLQ-C30 data were available for 0, 3, 6 and 12 months after initial treatment commenced. We mapped the EORTC QLQ-C30 data to EQ-5D health utilities using the algorithm from McKenzie and van der Pol.107 For the first three periods, the EQ-5D utility scores were similar for both CTDa and MP groups, and similar to those from Gulbrandsen and colleagues.91 (AiC/CiC information has been removed.)

In the model we estimate the utility for the post-treatment health state (until disease progression) as a weighted average of those who had a CR (AiC/CiC information has been removed) and those with a lesser response (AiC/CiC information has been removed).

Estimation of costs

Drug costs

Drug unit costs and doses were based on the BNF (No. 57).35 Duration of treatment was based on recommendations from the SPC,29,33 expert clinical opinion and the published trials. A summary of the dose and duration of treatment for each of the comparators is given in Table 38.

TABLE 38. Summary data for treatment duration, dose and unit cost.

TABLE 38

Summary data for treatment duration, dose and unit cost.

The duration of treatment varied between seven cycles for CTDa and nine cycles for VMP. We assumed that MP would be given for the same number of cycles as thalidomide and bortezomib when it was given in combination with them. The SPC of thalidomide states that a maximum number of 12 cycles of 6 weeks each should be used, as used in the trial by Facon and colleagues.23 However, one of our clinical experts advised that a shorter duration of eight cycles was more representative of clinical practice.

The dose of thalidomide was assumed to be 150 mg, based upon the dosages used in the IFM RCT (100 mg)59 and the MMIX RCT (200 mg).49 The dose recommended by the SPC is 200 mg per day, but one of our clinical experts advised that, in practice, few patients are able to tolerate such a high dose. Bortezomib is administered as a 3- to 5-second bolus intravenous injection. The cost of the 3.5-mg vial is £762.68. The cost of bortezomib administration was £153.40.100

The total cost for bortezomib depends on the wastage from the vial. In the NICE appraisal of bortezomib for relapsed MM,30 the appraisal committee considered the issue of vial sharing. They expressed a number of concerns including issues related to maintenance of best aseptic practice and the practical constraints of patient numbers and geographical locations of myeloma centres. The Committee was not convinced that vial sharing could be considered either safe or routinely achievable in practice across the NHS.

One of our clinical experts advised that they attempted to administer bortezomib in groups of three persons to minimise wastage. However, this may not be possible in smaller units. In the base-case analysis we assumed that only one vial would be used per patient and then varied this assumption in a scenario analysis.

Patients on thalidomide also received thromboprophylaxis for 5 months in the form of low-molecular-weight heparin (dalteparin 5000 units once daily subcutaneously)28 at a total cost of £428.88. In addition to chemotherapy, patients also require treatment with other medication, such as bisphosphonates, but the cost for these was assumed to be similar across all interventions, and has therefore not been included in the model costs.

Second-line treatment

Following disease progression after first-line therapy, patients receive second-line treatment. Based on clinical advice, NICE guidance,30 trial data and assumptions used in the Janssen–Cilag submission, it was assumed that most individuals would receive bortezomib as second-line therapy unless they had already received it as first-line therapy. HDD and CTDa were also used as these are common second-line treatments in the UK.30 Most patients who had VMP as first-line treatment had CTDa as second-line treatment. The dose for HDD was 40 mg per day and the cost of treatment was £189.31. The assumed distribution of second-line treatments following first-line treatment is shown in Table 39. For all treatments, 60% of patients received second-line treatment, based upon the number of patients still alive at the time corresponding to mean PFS.

TABLE 39. Distribution of second-line treatments following first-line treatment.

TABLE 39

Distribution of second-line treatments following first-line treatment.

Consultations

Based on clinical advice, we assumed patients receive on average one consultation every month during their treatment period and one consultation every three months thereafter. The outpatient consultation cost was £121.11 (reference cost code 370: medical oncology follow-up consultation).100

Monitoring tests

The monitoring tests used for the management of MM, based on those used for the MMIX RCT,49 are shown in Table 40 with their unit costs.

TABLE 40. Monitoring tests completed at each outpatient appointment for MM.

TABLE 40

Monitoring tests completed at each outpatient appointment for MM.

Adverse events

For each comparator, the incidence of AEs was estimated using evidence from the RCTs included in our systematic review of clinical effectiveness (see Chapter 4, Adverse events). AEs included in the model were treatment-related serious (grades 3 and 4) AEs and the incidence was taken from the VISTA trial26 for VMP, from the IFM 99/06 trial for MPT23 and from the MMIX trial for CTDa. The IFM 99/06 trial was used for MPT as this trial had more comprehensive reporting than the other MPT trials. For MP, a weighted average was calculated using data from the MP arm from each of these trials.

Although AE data is consistently reported across studies as percentage patients, the types of AEs reported differed between the studies. This summary extracts key AEs (haematological, gastrointestinal, infections, neuropathy and thrombosis) for use within the model (and is not a comprehensive analysis of all AEs). Gastrointestinal AE numbers for MMIX were calculated from constipation grades 3 and 4 as reported and other gastrointestinal AEs (grade not specified but proportion calculated for grades 3 and 4). Total infection for the VISTA study was calculated by totalling figures for pneumonia and herpes zoster (which assumes that there were no others). Infections were not specified for other studies. The definition of haematological AEs may not be exactly consistent across studies but gives an indication of possible rates for thrombocytopenia/cytopenia. AE data were not available for the MMIX RCT for the incidence of neutropenia and anaemia and for these AEs we have assumed the same incidence for CTDa as for MPT. Where events of grades 3 and 4 were not reported separately, we assumed there were twice as many grade 3 as grade 4 events, as this was the ratio for the total numbers of grade 3 and 4 AEs.

The unit costs of treating AEs were estimated, based on those used in a NICE technology appraisal for lenalidomide (TA171)31 and the Celgene MS [see Review of the Celgene submission to NICE (Thalidomide) and Appendix 12]. The NICE technology appraisal for lenalidomide31 collected information on the proportion of patients who would receive treatment, the location where treatment would be administered, and treatments administered for each specific disease-related complication. The unit cost of inpatient and day-case treatment for the AE was calculated from CHKS (Caspe Healthcare Knowledge Systems) data, which contains individual patient-level data from most UK hospital trusts, and NHS reference cost data. This report did not include all relevant AE costs. The Celgene MS used a similar methodology to calculate unit costs and these were used for AEs of infection, dizziness or fatigue (Table 41). There was no distinction made in that report between the costs of grade 3 and 4 AEs and so for these AEs we have assumed equal costs for grades 3 and 4. We used the cost of diarrhoea for the cost of gastrointestinal AEs as this cost was between the costs of nausea and constipation. The unit costs for treating the AEs are shown in Table 42.

TABLE 41. Incidence of AEs at grades 3 and 4 reported for different treatments.

TABLE 41

Incidence of AEs at grades 3 and 4 reported for different treatments.

TABLE 42. Unit costs for treating AEs at grades 3 and 4.

TABLE 42

Unit costs for treating AEs at grades 3 and 4.

The total costs of treating AEs were estimated by multiplying each AE incidence by the appropriate unit cost for that AE.

Results of SHTAC independent economic evaluation

This section reports the cost-effectiveness results for a typical person with MM who received treatment with bortezomib in combination with MP or thalidomide in combination with MP compared with those receiving MP. Results for costs and QALYs are presented for each treatment, with costs and benefits discounted at 3.5%.78 The survival curves for OS from the model are shown in Figure 11. The results show increased survival for MPT, VMP and CTDa versus MP. The cost-effectiveness is presented as incremental cost per QALY compared with existing treatment with MP. The summary results of the non-discounted treatment effects are shown in Table 43. In the base-case analysis, OS varied from 4.20 years for MP to 6.66 years for MPT. Survival for MPT is slightly longer than for VMP. The cost-effectiveness results for CTDa should be treated with caution, (AiC/CiC information has been removed). The summary results of the undiscounted costs are shown in Table 44 for each treatment. First-line treatment costs ranged from £112 for MP to £43,824 for VMP. Second-line treatment costs were the same for MP, MPT and CTDa, and about £10,000 lower for VMP. The total costs of the treatments ranged from £23,248 for MP to £59,644 for VMP.

FIGURE 11. Overall survival curves for MP, MPT, VMP and CTDa.

FIGURE 11

Overall survival curves for MP, MPT, VMP and CTDa.

TABLE 43. Summary of the undiscounted duration in each health state for treatment with MP, MPT, VMP and CTDa.

TABLE 43

Summary of the undiscounted duration in each health state for treatment with MP, MPT, VMP and CTDa.

TABLE 44. Summary of the undiscounted costs for treatment with MP, MPT, VMP and CTDa.

TABLE 44

Summary of the undiscounted costs for treatment with MP, MPT, VMP and CTDa.

The baseline discounted cost-effectiveness results are shown in Table 45. Each of the treatments is more expensive than MP, with the additional cost ranging from £8,600 (CTDa) to more than £35,000 (VMP) over a patient lifetime. The incremental cost-effectiveness versus MP for MPT, VMP and CTDa figures are £9135, £29,820 and £33,031 per QALY gained, respectively.

TABLE 45. Baseline summary of discounted cost-effectiveness results.

TABLE 45

Baseline summary of discounted cost-effectiveness results.

Each comparator is presented in successive rows ordered by the number of QALYs generated. Each option is then compared to the next best option. In summary the incremental analysis suggests extended dominance of MPT over CTDa, and MPT dominates VMP as it is more effective and cheaper (Figure 12). The comparison of VMP versus MPT suggests that VMP and CTDa are unlikely to be cost-effective treatment options at the conventional willingness-to-pay threshold of £20,000–30,000 per QALY gained. However, there is much uncertainty around the results for CTDa because the OS effectiveness estimates were not statistically significant and the results from the MMIX RCT included those of participants who had received thalidomide maintenance therapy.

FIGURE 12. Cost-effectiveness plane for treatments MP, CTDa, VMP and MPT.

FIGURE 12

Cost-effectiveness plane for treatments MP, CTDa, VMP and MPT.

Sensitivity analysis

Deterministic sensitivity analysis

One-way deterministic sensitivity analyses were performed, in which model parameters were systematically and independently varied, using a realistic minimum and maximum value.

The sensitivity analysis investigated the effect of uncertainty around the model assumptions, structure and parameter values on the cost-effectiveness results, in order to highlight the most influential parameters. The effects of uncertainty in multiple parameters were addressed using PSA, which is reported later in this chapter (see Probabilistic sensitivity analysis). Where possible, the parameters were varied according to the ranges of the CIs of these parameters, based on the published estimates. Where these data were not available an alternative suitable range was chosen. The same ranges were used in the deterministic analyses and PSA and these are described in Appendix 14.

Tables 4648 show the results of the deterministic sensitivity analyses for each of the treatments versus MP for the most influential parameters. Other parameters, such as AE cost, CR rate and utility values, were varied in the sensitivity analyses but were found to only have a negligible effect on the results. The cost-effectiveness results are fairly robust to changes in parameters in the deterministic sensitivity analysis. For each of the treatments, the model results are most sensitive to the HR for OS, cost and dosage of the treatment and the overall baseline survival curve used for MP. The deterministic sensitivity results for MPT versus MP are shown in Table 46 and varied between £6445 and £22,749 per QALY gained. MPT dominates VMP for all parameters, except the VMP treatment effectiveness for OS (HR). Using the higher CI for OS, the cost-effectiveness estimate of VMP versus MPT is £44,928 per QALY gained.

TABLE 46. Deterministic sensitivity analyses for MPT vs MP.

TABLE 46

Deterministic sensitivity analyses for MPT vs MP.

TABLE 48. Deterministic sensitivity analyses for CTDa vs MP.

TABLE 48

Deterministic sensitivity analyses for CTDa vs MP.

The deterministic sensitivity results for VMP versus MP are shown in Table 47 and varied between £20,440 and £87,665 per QALY gained. VMP is dominated by MPT for all parameters, except the MPT treatment effectiveness for OS (HR). This is also the case if the model assumes that vials for bortezomib can be shared, rather than assuming one vial per patient. Using the lower CI for OS, the cost-effectiveness estimate of VMP versus MPT is £34,015 per QALY gained.

TABLE 47. Deterministic sensitivity analyses for VMP vs MP.

TABLE 47

Deterministic sensitivity analyses for VMP vs MP.

The deterministic sensitivity results for CTDa versus MP are shown in Table 48 and varied between −£29,210 and £16,897 per QALY gained. (AiC/CiC information has been removed.)

Scenario analysis

In addition to the sensitivity analyses four alternative scenarios were undertaken to investigate the uncertainty around structural assumptions (Table 49).

TABLE 49. Cost-effectiveness results for scenario analyses A–D.

TABLE 49

Cost-effectiveness results for scenario analyses A–D.

Scenario A. no subsequent therapies

The base-case scenario included the cost of second-line therapy. This scenario investigates the cost-effectiveness of first-line therapy only without including the subsequent treatment costs. In this case, MPT and CTDa are slightly less cost-effective versus MP, and VMP is considerably less cost-effective. The cost-effectiveness estimate for VMP versus MP increases to £37,711 per QALY gained. MPT continues to dominate VMP.

Scenario B. vial sharing

The base-case scenario assumes that it is not possible for patients to share vials of bortezomib. This scenario investigates the cost-effectiveness where patients do share vials of bortezomib. With vial sharing and no wastage, bortezomib becomes more cost-effective versus MP, with an ICER of £22,533 per QALY gained. MPT continues to dominate VMP.

Scenario C. inclusion of thalidomide maintenance trials

The base-case scenario uses the efficacy for MPT using only RCTs that did not include thalidomide maintenance. This scenario investigates the cost-effectiveness using the estimate for MPT efficacy from a meta-analysis that includes trials with thalidomide maintenance. Janssen– Cilag conducted a MTC for MPT efficacy with trials that included thalidomide maintenance and derived a HR (AiC/CiC information has been removed) for MPT versus MP. Using this HR makes MPT less cost-effective with an ICER of £24,276 per QALY gained versus MP. In addition, MPT no longer dominates VMP, with an ICER of £32,774 for VMP versus MPT.

Scenario D. treatment effectiveness beyond the end of trial

The base-case scenario extrapolates beyond the end of the trial by assuming a constant HR for the treatment effectiveness compared with MP. Although this is a standard methodological assumption, it is unclear how the treatment effectiveness changes beyond the end of the trial. This scenario investigates an alternative assumption whereby there is no treatment benefit for VMP, MPT and CTDa over MP, i.e. the event rates for these treatments are the same as for MP after the end of the trial. Using this assumption has a large effect on the model results, and all treatments are less cost-effective compared with MP. The ICERs for each of the treatment options more than double to £20,605 (MPT), £71,223 (VMP) and £80,382 (CTDa) per QALY gained versus MP. MPT continues to dominate VMP.

There are two additional scenario analyses for treatment duration and treatment discontinuations in Appendix 15.

Probabilistic sensitivity analysis

In the PSA, all parameters were sampled probabilistically from an appropriate distribution using similar ranges as used in the deterministic sensitivity analyses. The parameters sampled were discount rate, number of treatment cycles, utility values, CR rate, cost of AEs, parameters for the survival curves and the proportions of patients receiving bortezomib as second-line therapy. The distribution assigned to each variable included in the PSA and the parameters of the distributions are reported in Appendix 14.

One thousand simulations were run. The PSA results are presented in Table 50 and show similar results to the deterministic analyses (Tables 4648). The scatter plots for cost and health outcomes for the treatment options for the PSA are shown in Figure 13. The CEAC is shown in Figure 14, and indicates that at the £20,000 and £30,000 willingness-to-pay thresholds MPT has the highest probability of being cost-effective of 0.95 and 0.95, respectively.

TABLE 50. Baseline PSA cost-effectiveness results vs MP.

TABLE 50

Baseline PSA cost-effectiveness results vs MP.

FIGURE 13. Scatter plots of the costs and health benefits from PSA for MP, MPT, VMP and CTDa.

FIGURE 13

Scatter plots of the costs and health benefits from PSA for MP, MPT, VMP and CTDa.

FIGURE 14. Cost-effectiveness acceptability curve from the PSA.

FIGURE 14

Cost-effectiveness acceptability curve from the PSA.

Summary of cost-effectiveness

  • A systematic search of the literature found five abstracts of economic evaluations of treatment for patients with previously undiagnosed MM, who were ineligible for HDT-SCT. None of the studies contained sufficient information for critical appraisal. Three of the abstracts compared MPT with MP in patients in Scotland, Wales and Australia. Each abstract concluded that MPT was a cost-effective alternative to MP. Two abstracts compared VMP, MPT and MP in Canadian and US patients. Both studies concluded that the VMP regimen was cost-effective compared with MP and MPT. The latter study stated that VMP dominated MPT (i.e. more effective at a lower cost). All studies were industry funded.
  • A systematic review of studies of QoL for patients with MM identified six studies: only two of these studies were for the population of interest and both studies did not include generic preference-based utility measures; the other four QoL studies provided utility estimates for patients with MM who had intensive therapy.
  • Two manufacturers submitted evidence to be considered for the appraisal of bortezomib and thalidomide treatment. Janssen–Cilag, the manufacturer of bortezomib, constructed a survival model that estimated OS and PFS based on treatment effects from a MTC of the RCTs. They included second- and third-line treatment. The base-case results from the submission found all treatments (VMP, MPT and CTDa) to be cost-effective. The ICER for VMP versus MP is estimated to be £10,498. Furthermore, the ICERs of VMP versus MPT and VMP versus CTDa are estimated to be £11,907 and £10,411, respectively.
  • Celgene, the manufacturer of thalidomide, constructed a Markov model with health states for preprogression (with or without AEs), post progression and death. They assumed that survival after disease progression was the same irrespective of first-line treatment. Treatment effects for disease progression were calculated from a random effects MTC. The base-case results from the submission estimated an ICER of £23,381 per QALY gained for MPT versus MP and £303,845 per QALY for VMP versus MPT.
  • The authors of this report developed an independent survival model. The survival model consisted of two survival curves which estimated the mean time to death and disease progression. These survival durations were used to derive the time spent in three health states: treatment, post treatment and progression. Utility values were applied to these health states to estimate total QALYs for each treatment option. Costs were included for medications and outpatient costs and AEs. The model base-case results showed increased survival for each of the treatments compared with MP at an increased cost. The OS was marginally longer for MPT than for VMP at a considerably lower cost. The cost-effectiveness estimates for MPT, VMP and CTDa versus MP were £9135, £29,820 and £33,031 per QALY gained, respectively. However, MPT dominated VMP as it was cheaper and more effective.
  • The effects of a range of parameter values in the economic model were evaluated in sensitivity analyses. The model results were found to be robust to changes in the parameter values. The model results are most sensitive to changes in the parameter values of the HRs for OS.
  • The PSA estimated the probability of each of the treatments to be cost-effective at the £20,000 and £30,000 willingness-to-pay thresholds. MPT has the highest probability of being cost-effective, with probabilities of 0.95 and 0.95, respectively.
© 2011, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Cover of The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation
The Clinical Effectiveness and Cost-Effectiveness of Bortezomib and Thalidomide in Combination Regimens with an Alkylating Agent and a Corticosteroid for the First-Line Treatment of Multiple Myeloma: A Systematic Review and Economic Evaluation.
Health Technology Assessment, No. 15.41.
Picot J, Cooper K, Bryant J, et al.
Southampton (UK): NIHR Journals Library; 2011 Dec.

PubMed Health Blog...

read all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...