The cost-effectiveness of changes to the care pathway used to identify depression and provide treatment amongst people with diabetes in England: a model-based economic evaluation.

BACKGROUND: Diabetes is associated with premature death and a number of serious complications. The presence of comorbid depression makes these outcomes more likely and results in increased healthcare costs. The aim of this work was to assess the health economic outcomes associated with having both diabetes and depression, and assess the cost-effectiveness of potential policy changes to improve the care pathway: improved opportunistic screening for depression, collaborative care for depression treatment, and the combination of both. METHODS: A mathematical model of the care pathways experienced by people diagnosed with type-2 diabetes in England was developed. Both an NHS perspective and wider social benefits were considered. Evidence was taken from the published literature, identified via scoping and targeted searches. RESULTS: Compared with current practice, all three policies reduced both the time spent with depression and the number of diabetes-related complications experienced. The policies were associated with an improvement in quality of life, but with an increase in health care costs. In an incremental analysis, collaborative care dominated improved opportunistic screening. The incremental cost-effectiveness ratio (ICER) for collaborative care compared with current practice was £10,798 per QALY. Compared to collaborative care, the combined policy had an ICER of £68,017 per QALY. CONCLUSIONS: Policies targeted at identifying and treating depression early in patients with diabetes may lead to reductions in diabetes related complications and depression, which in turn increase life expectancy and improve health-related quality of life. Implementing collaborative care was cost-effective based on current national guidance in England.

Gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in breast cancer management: a systematic review and cost-effectiveness analysis.

BACKGROUND: Gene expression profiling (GEP) and expanded immunohistochemistry (IHC) tests aim to improve decision-making relating to adjuvant chemotherapy for women with early breast cancer. OBJECTIVE: The aim of this report is to assess the clinical effectiveness and cost-effectiveness of nine GEP and expanded IHC tests compared with current prognostic tools in guiding the use of adjuvant chemotherapy in patients with early breast cancer in England and Wales. The nine tests are BluePrint, Breast Cancer Index (BCI), IHC4, MammaPrint, Mammostrat, NPI plus (NPI+), OncotypeDX, PAM50 and Randox Breast Cancer Array. DATA SOURCES: Databases searched included MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE and The Cochrane Library. Databases were searched from January 2009 to May 2011 for the OncotypeDX and MammaPrint tests and from January 2002 to May 2011 for the other tests. REVIEW METHODS: A systematic review of the evidence on clinical effectiveness (analytical validity, clinical validity and clinical utility) and cost-effectiveness was conducted. An economic model was developed to evaluate the cost-effectiveness of adjuvant chemotherapy treatment guided by four of the nine test (OncotypeDX, IHC4, MammaPrint and Mammostrat) compared with current clinical practice in England and Wales, using clinicopathological parameters, in women with oestrogen receptor-positive (ER+), lymph node-negative (LN-), human epidermal growth factor receptor type 2-negative (HER2-) early breast cancer. RESULTS: The literature searches for clinical effectiveness identified 5993 citations, of which 32 full-text papers or abstracts (30 studies) satisfied the criteria for the effectiveness review. A narrative synthesis was performed. Evidence for OncotypeDX supported the prognostic capability of the test. There was some evidence on the impact of the test on decision-making and to support the case that OncotypeDX predicts chemotherapy benefit; however, few studies were UK based and limitations in relation to study design were identified. Evidence for MammaPrint demonstrated that the test score was a strong independent prognostic factor, but the evidence is non-UK based and is based on small sample sizes. Evidence on the Mammostrat test showed that the test was an independent prognostic tool for women with ER+, tamoxifen-treated breast cancer. The three studies appeared to be of reasonable quality and provided data from a UK setting (one study). One large study reported on clinical validity of the IHC4 test, with IHC4 score a highly significant predictor of distant recurrence. This study included data from a UK setting and appeared to be of reasonable quality. Evidence for the remaining five tests (PAM50, NPI+, BCI, BluePrint and Randox) was limited. The economic analysis suggests that treatment guided using IHC4 has the greatest potential to be cost-effective at a £20,000 threshold, given the low cost of the test; however, further research is needed on the analytical validity and clinical utility of IHC4, and the exact cost of the test needs to be confirmed. Current limitations in the evidence base produce significant uncertainty in the results. OncotypeDX has a more robust evidence base, but further evidence on its impact on decision-making in the UK and the predictive ability of the test in an ER+, LN-, HER- population receiving current drug regimens is needed. For MammaPrint and Mammostrat there were significant gaps in the available evidence and the estimates of cost-effectiveness produced were not considered to be robust by the External Assessment Group. LIMITATIONS: Methodological weaknesses in the clinical evidence base relate to heterogeneity of patient cohorts and issues arising from the retrospective nature of the evidence. Further evidence is required on the clinical utility of all of the tests and on UK-based populations. A key area of uncertainty relates to whether the tests provide prognostic or predictive ability. CONCLUSIONS: The clinical evidence base for OncotypeDX is considered to be the most robust. The economic analysis suggested that treatment guided using IHC4 has the most potential to be cost-effective at a threshold of £20,000; however, the evidence base to support IHC4 needs significant further research. STUDY REGISTRATION: PROSPERO 2011:CRD42011001361, available from www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001361.

Rituximab for the first-line treatment of stage III-IV follicular lymphoma (review of Technology Appraisal No. 110): a systematic review and economic evaluation.

BACKGROUND: Follicular lymphoma (FL) is a non-Hodgkin's lymphoma which typically presents when the disease is at an advanced stage. The majority of patients receive first-line therapy of rituximab in combination with chemotherapy, with two-thirds receiving cyclophosphamide, vincristine and prednisolone. The clinical and cost-effectiveness of other chemotherapies in combination with rituximab in first-line therapy is not known. OBJECTIVE: To systematically evaluate and appraise the clinical effectiveness and cost-effectiveness of rituximab (MabThera(®), Roche Products) in combination with chemotherapy, compared with chemotherapy alone, for the first-line treatment of symptomatic stage III-IV FL. DATA SOURCES: A systematic review of literature and an economic evaluation were carried out. Key databases [including MEDLINE In-Process & Other Non-Indexed Citations; Cumulative Index to Nursing and Allied Health Literature (CINAHL); EMBASE; The Cochrane Library, including the Cochrane Database of Systematic Reviews (CDSR), Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), NHS Economic Evaluation Database (NHS EED) and Health Technology Assessment (HTA) databases; Science Citation Index (SCI); and BIOSIS], plus research registers and conference proceedings, were searched for relevant studies from inception up to October 2010. REVIEW METHODS: One reviewer assessed titles and abstracts of studies identified by the search strategy, obtained the full text of relevant papers and screened them against inclusion criteria. Data from included studies were extracted by one reviewer using a standardised data extraction form and checked by a second reviewer. The quality of included studies was assessed by one reviewer and checked by a second. A patient-level simulation model was developed to estimate the costs and quality-adjusted life-year (QALY) gains from the perspective of the UK NHS and Personal Social Services, with costs and benefits discounted at 3.5% annually. RESULTS: Four randomised controlled trials comparing rituximab plus chemotherapy (R-chemotherapy) with chemotherapy alone in untreated, symptomatic patients with stage III-IV FL were identified. R-chemotherapy compared with chemotherapy alone increased the likelihood of a response to treatment in all four trials, with no additional toxicity of clinical relevance. Overall response rates were significantly improved in all four trials, with a difference between the R-chemotherapy and chemotherapy arms of between 5% and 24%, respectively. Complete response rates were also improved, with a difference between the R-chemotherapy and chemotherapy arms of between 2% and 25%, respectively. Exploratory meta-analyses were conducted; the level of statistical heterogeneity was very high and thus we believe the response rates from the individual trials to be a more robust estimator of the efficacy of the specific R-chemotherapy regimens. Over a follow-up period of 4-5 years, R-chemotherapy significantly increased the overall survival rate compared with chemotherapy alone in three trials, although data for two trials were compromised owing to the use of additional treatments. The incremental cost-effectiveness ratio (ICER) for the addition of rituximab to CVP (cyclophosphamide, vincristine and prednisolone), CHOP (cyclophosphamide, doxorubicin/adriamycin, vincristine and prednisolone) and MCP [mitoxantrone, chlorambucil (Leukeran(®), Aspen) and prednisolone] was £7720, £10,834 and £9316 per QALY gained, respectively, when it was assumed that first-line rituximab maintenance was not used. A scenario analysis is also presented, assuming that responders to R-chemotherapy in first-line induction receive maintenance with rituximab, increasing the ICER to £14,959, £21,687 and £20,493 per QALY gained, respectively. LIMITATIONS: These relate to the sources of data used for the effectiveness in first and second line and the assumed utility values; there is uncertainty about the effect of salvage treatment on patients who had been previously treated with an anthracycline regimen. There is uncertainty whether or not rituximab is as effective in second-line treatment when patients have been previously treated with rituximab. CONCLUSIONS: The results from four randomised trials comparing R-chemotherapy with chemotherapy alone showed an improvement in clinical effectiveness outcomes, with minimal clinically relevant additional adverse events or toxicity. The cost per QALY gained is estimated to be < £25,000 for all three comparisons under our base-case assumption and is considerably lower if first-line rituximab maintenance is not assumed. More data on patients pre-treated with rituximab and on the effect of first-line maintenance with rituximab is required for future work. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Prescribing high-dose lipid-lowering therapy early to avoid subsequent cardiovascular events: is this a cost-effective strategy?

BACKGROUND: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients. METHODS AND RESULTS: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative. CONCLUSION: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.

Trabectedin for the treatment of relapsed ovarian cancer.

The paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of trabectedin for the treatment of relapsed platinum-sensitive ovarian cancer, based upon a review of the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submission addressed only part of the decision problem and did not provide evidence to compare trabectedin (Yondelis®, PharmaMar) and pegylated liposomal doxorubicin hydrochloride (PLDH) (Caelyx®, Schering-Plough) with key comparators. The submission's direct comparison evidence came from one reasonable-quality randomised controlled trial (RCT) of trabectedin and PLDH versus PLDH alone (ET743-OVA-301). The results of the RCT were subdivided into the entire platinum-sensitive population (> 6-month relapse after initial platinum-based chemotherapy) and partially platinum-sensitive (≥ 6- to 12-month relapse) and fully platinum-sensitive (> 12-month relapse) populations. The outcomes included were overall survival, progression-free survival measured by three types of assessor, response rates, adverse effects of treatment, health-related quality of life and cost per quality-adjusted-life-year (QALY) gained. A mixed treatment comparison (MTC) meta-analysis comparing trabectedin and PLDH with single-agent PLDH within the entire platinum-sensitive population, with paclitaxel or with topotecan also formed part of the submission. The RCT data showed that trabectedin plus PLDH compared with PLDH monotherapy had a significant effect on overall survival only within the partially platinum-sensitive subgroup. PFS results reported by the independent radiologists showed significant effects in favour of the trabectedin and PLDH arm for the entire and partially platinum-sensitive populations only. Rates of grade 3 and 4 adverse events were mostly higher in the trabectedin and PLDH arm than in the PLDH alone arm. There were several issues regarding the undertaking of the MTC, and thus the data were not considered robust. Furthermore, the ERG did not believe the MTC to be necessary to answer the decision problem. The manufacturer submitted a de novo cost-effectiveness model. The main analysis compared trabectedin in combination with PLDH versus paclitaxel, topotecan and PLDH (each as monotherapy) in the entire platinum-sensitive population, using results estimated from the MTC. Additional analyses were presented comparing trabectedin in combination with PLDH versus PLDH monotherapy using direct evidence from the OVA-301 trial for the fully, partially and entire platinum-sensitive populations. The cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was estimated to be £ 70,076 in the main analysis. In the additional analyses, the cost per QALY gained for trabectedin in combination with PLDH versus PLDH monotherapy was £ 94,832, £ 43,996 and £ 31,092 for the entire, partially and fully platinum-sensitive populations, respectively. Additional work was undertaken by the ERG using patient-level data and amending some assumptions to provide a better statistical fit to the Kaplan-Meier data than the exponential distribution assumed by the manufacturer. The ERG base-case estimate of the cost per QALY of trabectedin in combination with PLDH ranged from £46,503 to £54,607 in the partially platinum-sensitive population. At the time of writing, trabectedin in combination with PLDH for the treatment of women with relapsed platinum-sensitive ovarian cancer is not recommended by NICE in the final appraisal determination.

Trabectedin for the treatment of advanced metastatic soft tissue sarcoma.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of trabectedin for the treatment of advanced metastatic soft tissue sarcoma, in accordance with the licensed indication, based on the evidence submission from the manufacturer to NICE as part of the single technology appraisal (STA) process. The outcomes stated in the manufacturer's definition of the decision problem were overall survival (OS), progression-free survival (PFS), response rates, adverse effects of treatment, health-related quality of life, and cost per quality-adjusted life-year (QALY) gained. The clinical evidence was derived from one randomised controlled trial (RCT), in which the licensed dose of trabectedin was compared with a different dose of trabectedin, and three phase II studies. In the RCT, the median OS was 13.9 months for the licensed dose of trabectedin, which was not significantly different from that for the comparator dose of trabectedin, which was 11.8 months. From the phase II uncontrolled trials, median OS was reported as 9.2 or 12.8 months. The RCT reported significantly superior PFS for the licensed dose of trabectedin (median 3.3 months) over the comparator trabectedin dose (median 2.3 months). One phase II uncontrolled trial reported median PFS as 1.9 months in the licensed dose of trabectedin. The RCT reported PFS rates at 6 months were 35.5% for the licensed dose of trabectedin, and 27.5% for the comparator dose of trabectedin. From the phase II uncontrolled trials, PFS rates at 6 months were 24.4% or 29%. For the RCT, deaths attributed to trabectedin occurred in 3.1% of the licensed dose, and 2.3% of the comparator group. The most common severe adverse events were neutropenia, although with a low rate of febrile neutropenia, thrombocytopenia, and aspartate aminotransferase and alanine aminotransferase elevation, although these were reported to be non-cumulative and reversible. Following dialogue iterations with the ERG team, the manufacturer revised the model twice. However, despite revisions, errors/inconsistencies were found in the latest version of the model and were corrected by the ERG (only for the base case). In the latest manufacturer's submission, the cost per QALY gained of trabectedin compared with best supportive care (BSC) was estimated to be 56,985 pounds for the base case using effectiveness from the STS (Soft Tissue Sarcomas)-201 trial for trabectedin and a pool analysis of the European Organisation for Research and Treatment of Cancer data set for BSC. This analysis was constrained to patients with L-sarcomas only. When the joint uncertainty between parameters was considered, the cost-effectiveness acceptability curve showed that trabectedin has a very low probability of being cost-effective at a threshold of 30,000 pounds per QALY gained compared with BSC for any scenario. The guidance has yet to be issued by NICE.

Autologous haematopoietic stem cell transplantation for secondary progressive multiple sclerosis: an exploratory cost-effectiveness analysis.

Treatment options for secondary progressive multiple sclerosis (SPMS) are limited. Mitoxantrone is routinely used to stabilize disease progression; however, evolving evidence suggests clinical benefit from intensive treatment with autologous haematopoietic stem cell transplantation (HSCT). Given differences in cost and outcomes, preliminary cost-effectiveness studies are warranted if this approach is to be developed for more widespread application in SPMS. We developed a decision-analytic Markov model to explore the potential cost-effectiveness of autologous HSCT versus mitoxantrone in SPMS, using patient-level data from registry sources. The model evaluates the lifetime costs and health outcomes associated with disability progression and relapse. Sensitivity analyses were undertaken to examine the uncertainty surrounding cost-effectiveness outcomes. In the absence of randomised controlled trial (RCT) evidence, conditions for comparative analysis were not ideal. Under optimistic assumptions, HSCT is estimated to cost below pound3000 per quality adjusted life year gained. However, when a strict 6-month sustained progression rule is adopted, HSCT may be less effective and more expensive than mitoxantrone. The model results were sensitive to reducing procedural costs and HSCT-related mortality. We conclude that HSCT could potentially achieve an acceptable level of cost-effectiveness. However, caution should be exercised as large, high-quality RCTs comparing HSCT versus mitoxantrone are necessary to validate these findings.

Early high-dose lipid-lowering therapy to avoid cardiac events: a systematic review and economic evaluation.

OBJECTIVE: To evaluate the cost-effectiveness of high-dose statins (atorvastatin 80 mg/day, rosuvastatin 40 mg/day and simvastatin 80 mg/day) versus simvastatin 40 mg/day in individuals with acute coronary syndrome (ACS). DATA SOURCES: Eleven bibliographic databases, including MEDLINE, CINAHL, EMBASE, Cochrane Database of Systematic Reviews, CENTRAL, DARE and NHS EED, were searched from inception to 2008. REVIEW METHODS: Data relating to study design, baseline patient characteristics, clinical or surrogate outcome, and adverse events were abstracted, and methodological quality was assessed according to standard methods. A synthesis of the available evidence was performed using a Bayesian mixed treatment meta-analysis using both direct and indirect evidence. An existing Markov model was modified to explore the costs and benefits associated with a lifetime of the differing treatment regimens. RESULTS: A total of 3345 titles and abstracts were screened for inclusion in the review of clinical effectiveness and 125 full papers retrieved and assessed in detail. Of these, 30 papers met the inclusion criteria for the review, describing 28 trials. The Bayesian mixed treatment meta-analysis demonstrated a clear dose-response relationship in terms of reductions in low-density lipoprotein cholesterol (LDL-c), with rosuvastatin 40 mg/day achieving the greatest percentage reduction (56%) from baseline, followed by atorvastatin 80 mg/day (52%), simvastatin 80 mg/day (45%) and simvastatin 40 mg/day (37%). Although serious adverse events with statins are rare, their incidence is likely to be greater with higher doses. Several clinical scenarios were used to explore the effect of adherence on the cost-effectiveness of the treatment regimens. Using a threshold of 20,000 pounds per quality-adjusted life-year (QALY) and assuming that the benefits and adherence rates observed in the clinical trials are generalisable to a clinical setting and that individuals who do not tolerate the higher-dose statins are prescribed simvastatin 40 mg/day, then simvastatin 80 mg/day, atorvastatin 80 mg/day and rosuvastatin 40 mg/day would be considered cost-effective compared with simvastatin 40 mg/day in individuals with ACS. Simvastatin 80 mg/day is not well tolerated because of the high incidence rates of less severe adverse events such as myopathy (26-fold higher than rates in those receiving simvastatin 20 mg/day), which are likely to affect adherence levels in clinical practice. The reference case shows that rosuvastatin is the optimal treatment for individuals with a recent history of ACS using a threshold of 20,000 pounds per QALY. However, this is based on the assumption that the additional incremental reductions in LDL-c observed in patients treated with rosuvastatin 40 mg/day compared with atorvastatin will transfer into corresponding changes in relative risks of cardiovascular events. CONCLUSIONS: Simvastatin 80 mg/day cannot be recommended because of the high incidence rates of adverse events. If the cost of atorvastatin decreases in line with that observed for simvastatin when the patent ends in 2011, atorvastatin 80 mg/day will be the most cost-effective treatment for all thresholds; if the cost reduces to 25% of the current value, atorvastatin 80 mg/day will be the most cost-effective treatment for thresholds between 5000 pounds and 30,000 pounds per QALY. Large long-term RCTs reporting effects in terms of clinical events are required to determine the optimum statin use for subgroups.