Cost-effectiveness of avelumab first-line maintenance therapy for adult patients with locally advanced or metastatic urothelial carcinoma in France.

BACKGROUND: This study evaluated the cost-effectiveness of avelumab first-line (1L) maintenance therapy plus best supportive care (BSC) versus BSC alone for adults with locally advanced or metastatic urothelial carcinoma (la/mUC) that had not progressed following platinum-based chemotherapy in France. METHODS: A three-state partitioned survival model was developed to assess the lifetime costs and effects of avelumab plus BSC versus BSC alone. Data from the phase 3 JAVELIN Bladder 100 trial (NCT02603432) were used to inform estimates of clinical and utility values considering a 10-year time horizon and a weekly cycle length. Cost data were estimated from a collective perspective and included treatment acquisition, administration, follow-up, adverse event-related hospitalization, transport, post-progression, and end-of-life costs. Health outcomes were measured in quality-adjusted life-years (QALYs) and life-years gained. Costs and clinical outcomes were discounted at 2.5% per annum. Incremental cost-effectiveness ratios (ICERs) were used to compare cost-effectiveness and willingness to pay in France. Uncertainty was assessed using a range of sensitivity analyses. RESULTS: Avelumab plus BSC was associated with a gain of 2.49 QALYs and total discounted costs of €136,917; BSC alone was associated with 1.82 QALYs and €39,751. Although avelumab plus BSC was associated with increased acquisition costs compared with BSC alone, offsets of -€20,424 and -€351 were observed for post-progression and end-of-life costs, respectively. The base case analysis ICER was €145,626/QALY. Sensitivity analyses were consistent with the reference case and showed that efficacy parameters (overall survival, time to treatment discontinuation), post-progression time on immunotherapy, and post-progression costs had the largest impact on the ICER. CONCLUSIONS: This analysis demonstrated that avelumab plus BSC is associated with a favorable cost-effectiveness profile for patients with la/mUC who are eligible for 1L maintenance therapy in France.

Challenges with Estimating Long-Term Overall Survival in Extensive Stage Small-Cell Lung Cancer: A Validation-Based Case Study.

Objective: The study aimed to explore methods and highlight the challenges of extrapolating the overall survival (OS) of immunotherapy-based treatment in first-line extensive stage small-cell lung cancer (ES-SCLC). Methods: Standard parametric survival models, spline models, landmark models, mixture and non-mixture cure models, and Markov models were fitted to 2-year data of the CASPIAN Phase 3 randomised trial of PD-L1 inhibitor durvalumab added to platinum-based chemotherapy (NCT03043872). Extrapolations were compared with updated 3-year data from the same trial and the plausibility of long-term estimates assessed. Results: All models used provided a reasonable fit to the observed Kaplan-Meier (K-M) survival data. The model which provided the best fit to the updated CASPIAN data was the mixture cure model. In contrast, the landmark analysis provided the least accurate fit to model survival. Estimated mean OS differed substantially across models and ranged from (in years) 1.41 (landmark model) to 4.81 (mixture cure model) for durvalumab plus etoposide and platinum and from 1.01 (landmark model) to 2.00 (mixture cure model) for etoposide and platinum. Conclusion: While most models may provide a good fit to K-M data, it is crucial to assess beyond the statistical goodness-of-fit and consider the clinical plausibility of the long-term predictions. The more complex cure models demonstrated the best predictive ability at 3 years, potentially providing a better representation of the underlying method of action of immunotherapy; however, consideration of the models' clinical plausibility and cure assumptions need further research and validation. Our findings underscore the significance of adopting a clinical perspective when selecting the most appropriate approach to model long-term survival, particularly when considering the use of more complex models.

Cost-effectiveness analysis of atezolizumab as adjuvant treatment of patients with stage II-IIIA non-small cell lung cancer, PD-L1+≥50% of tumor cells in France: A modeling study.

INTRODUCTION: The objective of this study was to assess the cost-effectiveness of atezolizumab versus best supportive care (BSC) as adjuvant treatment following resection and platinum-based chemotherapy for patients with stage II-IIIA non-small cell lung cancer (NSCLC) whose tumours have a programmed death-ligand 1 (PD-L1) expression ≥ 50% of tumour cells and excluding those with ALK/EGFR mutations, from a French collective perspective. MATERIAL AND METHODS: A five state Markov model over a 20-year time horizon was considered, including disease-free survival (DFS1) from IMpower010 trial, three progression states (locoregional recurrence, first and second-line metastatic recurrence) and death. Utilities, quality-adjusted life year (QALY) decrements associated to adverse events, costs, resource use, and transition probabilities were considered in the model. These inputs were sourced from IMpower010 trial, literature, and clinical experts' opinion. Model uncertainty was assessed through deterministic, probabilistic sensitivity analyses and scenario analyses. RESULTS: Atezolizumab was associated with a QALY gain of 1.662, mainly driven by additional time spent in the DFS state, and a life-year gain of 2.112 years. The incremental cost-effectiveness ratio (ICER) for atezolizumab versus BSC was €21,348/QALY gained. The sensitivity analyses highlighted that uncertainty within the model had limited impact on results. Changing the DFS survival curves to other plausible distributions produced ICERs below €20,000/QALY. Introducing an increasing proportion of cured patients (91.5%) from year two to year five reduced the ICER to €13,083/QALY, while including a loss of efficacy at year two in the atezolizumab treatment arm increased the ICER to €33,755/QALY. DISCUSSION: Atezolizumab as adjuvant treatment in stage II-IIIA NSCLC resected patients with PDL1 ≥ 50% and without ALK/EGFR mutations has a lower ICER than other oncology drugs in France and a similar ICER to other adjuvant treatment in oncology.

Cost-utility analysis of atezolizumab with bevacizumab in untreated unresectable or advanced hepatocellular carcinoma in France.

BACKGROUND AND AIMS: The IMbrave150 clinical trial assessed the efficacy and safety of atezolizumab in combination with bevacizumab (ATZ+BVA) versus sorafenib in adults with advanced/unresectable hepatocellular carcinoma, who have not received prior systemic treatment. Our aim was to assess the cost-effectiveness of ATZ+BVA versus sorafenib in France based on an updated prices and considering French National real-world data, to confirm the initial recommendations from the Heath Technology Assessment submission published in 2021, and provide additional visibility to decision-makers reflecting current clinical practice. METHODS: A partition survival model was developed to project clinical outcomes, quality of life, and costs of patients with HCC treated with ATZ+BVA versus sorafenib over a lifetime horizon. Survival outcomes were extrapolated via parametric functions for both treatment strategies. Quality of life (EQ-5D-5L, French tariffs) were sourced from IMbrave150. The Guyot method was considered as a scenario analysis by integrating retrospective real-world data extracted from the French Health Insurance Database to refine long term survival extrapolations. RESULTS: In the reference case, ATZ+BVA was associated with 0.61 additional Quality Adjusted Life Years (QALYs) compared to sorafenib (1.95 vs 1.35), and an incremental cost of €92,704. The incremental cost-utility ratio (ICUR) was 152,974 €/QALY gained. Adjusting the survival curves with French external evidence led to a 14% ICUR reduction (131,163 €/QALY). CONCLUSIONS: ATZ+BVA is a cost-effective strategy based on the range recently published for the value of a QALY in France and offers better chances of survival to patients.

Cost-effectiveness of dolutegravir/abacavir/lamivudine in HIV-1 treatment-Naive (TN) patients in France.

BACKGROUND: To evaluate the cost-effectiveness of an integrase inhibitor (INI), dolutegravir (DTG), in combination with abacavir (ABC)/lamivudine (3TC) in France, in treatment-naive (TN) HIV adult patients. METHODS: The ARAMIS microsimulation Markov model, evaluates costs and effects of DTG vs. first-line ARVs options including INIs (raltegravir, elvitegravir/c), protease inhibitors (PIs) (darunavir/r, atazanavir/r, lopinavir/r), non-nucleoside reverse transcriptase inhibitors (efavirenz and rilpivirine). Efficacy and safety data were derived from phase III studies and network meta-analysis. Treatment algorithms were based on French guidelines and experts opinion. Costs included routine HIV and opportunistic infection care, and death. RESULTS: The model showed the fixed-dose combination DTG/ABC/3TC was more effective than all other recommended regimens: patients stayed longer on first-line, and lived longer and healthier. With the exception of EFV, DTG/ABC/3TC was more efficacious and less costly compared to all strategies. The cost per QALY gained (ICER) for DTG compared to EFV was €6,939. DTG/ABC/3TC was more efficacious and less costly compared to INIs and PIs in all deterministic sensitivity analyses. CONCLUSION: DTG/ABC/3TC was cost-effective in the management of HIV TN patients in France. These results are mainly explained by its lower price compared to other INIs and PIs, DTG's superior efficacy and high barrier to resistance.

NEPA, a new fixed combination of netupitant and palonosetron, is a cost-effective intervention for the prevention of chemotherapy-induced nausea and vomiting in the UK.

BACKGROUND: The objective was to evaluate the cost-effectiveness of NEPA, an oral fixed combination netupitant (NETU, 300 mg) and palonosetron (PA, 0.5 mg) compared with aprepitant and palonosetron (APPA) or palonosetron (PA) alone, to prevent chemotherapy-induced nausea and vomiting (CINV) in patients undergoing treatment with highly or moderately emetogenic chemotherapy (HEC or MEC) in the UK. SCOPE: A systematic literature review and meta-analysis were undertaken to compare NEPA with currently recommended anti-emetics. Relative effectiveness was estimated over the acute (day 1) and overall treatment (days 1-5) phases, taking complete response (CR, no emesis and no rescue medication) and complete protection (CP, CR and no more than mild nausea [VAS scale <25 mm]) as primary efficacy outcomes. A three-health-state Markov cohort model, including CP, CR and incomplete response (no CR) for HEC and MEC, was constructed. A five-day time horizon and UK NHS perspective were adopted. Transition probabilities were obtained by combining the response rates of CR and CP from NEPA trials and odds ratios from the meta-analysis. Utilities of 0.90, 0.70 and 0.24 were defined for CP, CR and incomplete response, respectively. Costs included medications and management of CINV-related events and were obtained from the British National Formulary and NHS Reference Costs. The expected budgetary impact of NEPA was also evaluated. FINDINGS: In HEC patients, the NEPA strategy was more effective than APPA (quality-adjusted life days [QALDs] of 4.263 versus 4.053; incremental emesis-free and CINV-free days of +0.354 and +0.237, respectively) and was less costly (£80 versus £124), resulting in NEPA being the dominant strategy. In MEC patients, NEPA was cost effective, cumulating in an estimated 0.182 extra QALDs at an incremental cost of £6.65 compared with PA. CONCLUSION: Despite study limitations (study setting, time horizon, utility measure), the results suggest NEPA is cost effective for preventing CINV associated with HEC and MEC in the UK.

Comparison of cardiovascular risk algorithms in patients with vs without rheumatoid arthritis and the role of C-reactive protein in predicting cardiovascular outcomes in rheumatoid arthritis.

Objectives: The aims were to compare the performance of cardiovascular risk calculators, Framingham Risk Score (FRS) and QRISK2, in RA and matched non-RA patients and to evaluate whether their performance could be enhanced by the addition of CRP. Methods: We conducted a retrospective analysis, using a clinical practice data set linked to Hospital Episode Statistics (HES) data from the UK. Patients presenting with at least one RA diagnosis code and no prior cardiovascular events were matched to non-RA patients using disease risk scores. The overall performance of the FRS and QRISK2 was compared between cohorts, and assessed with and without CRP in the RA cohort using C-Index, Akaike Information Criterion (AIC) and the net reclassification index (NRI). Results: Four thousand seven hundred and eighty RA patients met the inclusion criteria and were followed for a mean of 3.8 years. The C-Index for the FRS in the non-RA and RA cohort was 0.783 and 0.754 (P < 0.001) and that of the QRISK2 was 0.770 and 0.744 (P < 0.001), respectively. Log[CRP] was positively associated with cardiovascular events, but improvements in the FRS and QRISK2 C-Indices as a result of inclusion of CRP were small, from 0.764 to 0.767 (P = 0.026) for FRS and from 0.764 to 0.765 (P = 0.250) for QRISK2. The NRI was 3.2% (95% CI: -2.8, 5.7%) for FRS and -2.0% (95% CI: -5.8, 4.5%) for QRISK2. Conclusion: The C-Index for the FRS and QRISK2 was significantly better in the non-RA compared with RA patients. The addition of CRP in both equations was not associated with a significant improvement in reclassification based on NRI.

Cardiovascular risk factor management in patients with RA compared to matched non-RA patients.

OBJECTIVE: RA is associated with a 50-60% increase in risk of cardiovascular (CV) death. This study aimed to compare management of CV risk factors in RA and matched non-RA patients. METHODS: A retrospective cohort study was conducted using UK clinical practice data. Patients presenting with an incident RA diagnosis were matched 1:4 to non-RA patients based on a propensity score for RA, entry year, CV risk category and treatment received at index date (date of RA diagnosis). Patients tested and treated for CV risk factors as well as those attaining CV risk factor management goals were evaluated in both groups. RESULTS: Between 1987 and 2010, 24 859 RA patients were identified and matched to 87 304 non-RA patients. At index date, groups had similar baseline characteristics. Annual blood pressure, lipids and diabetes-related testing were similar in both groups, although CRP and ESR were higher in RA patients at diagnosis and decreased over time. RA patients prescribed antihypertensives increased from 38.2% at diagnosis to 45.7% at 5 years, from 14.0 to 20.6% for lipid-lowering treatments and from 5.1 to 6.4% for antidiabetics. Similar treatment percentages were observed in non-RA patients, although slightly lower for antihypertensives. Modest (2%) but significantly lower attainment of lipid and diabetes goals at 1 year was observed in RA patients. CONCLUSION: There were no differences between groups in the frequency of testing and treatment of CV risk factors. Higher CV risk in RA patients seems unlikely to be driven by differences in traditional CV risk factor management.

Cost-Effectiveness of Dolutegravir in HIV-1 Treatment-Experienced (TE) Patients in France.

OBJECTIVES: To evaluate the cost-effectiveness of a new generation integrase inhibitor (INI), dolutegravir (DTG), in France, in treatment-experienced (TE) and INI-naïve HIV-infected adults with at least two classes resistance compared to raltegravir (RAL), by adapting previously published Anti-Retroviral Analysis by Monte Carlo Individual Simulation (ARAMIS) model. METHODS: ARAMIS is a microsimulation Markov model with a lifetime time horizon and a monthly cycle length. Health states are defined as with or without opportunistic infection and death. In the initial cohort, efficacy and safety data were derived from a phase III study comparing DTG to RAL. Antiretroviral treatment algorithms, accounting for patient history, were based on French guidelines and experts opinion. Costs are mainly including treatment costs, routine HIV and opportunistic infection care, and death. Utilities depend on CD4+ cell count and the occurrence of opportunistic infections. RESULTS: The ARAMIS model indicates in the TE population that DTG compared to RAL over a life time is associated with 0.35 additional quality-adjusted life years (QALY; 10.75 versus 10.41) and additional costs of €7,266 (€390,001 versus €382,735). DTG increased costs are mainly related to a 9.1-month increase in life expectancy for DTG compared with RAL, and consequently a longer time spent on ART. The incremental cost-effectiveness ratio (ICER) for DTG compared with RAL is €21,048 per QALY gained. About 83% and 14% of total lifetime costs are associated with antiretroviral therapy and routine HIV care respectively. Univariate deterministic sensitivity analyses demonstrate the robustness of the model. CONCLUSION: DTG is cost-effective in the management of TE INI naive patients in France, from a collective perspective. These results could be explained by the superior efficacy of DTG in this population and its higher genetic barrier to resistance compared to RAL. These data need to be confirmed with longer-term real life data.

A comparative analysis of two contrasting European approaches for rewarding the value added by drugs for cancer: England versus France.

OBJECTIVES: Within Europe, contrasting approaches have emerged for rewarding the value added by new drugs. In Ireland, The Netherlands, Sweden and the UK, the price of, and access to, a new drug has to be justified by the health gain it delivers compared with current therapy, typically expressed in quality-adjusted life-years (QALYs) gained. By contrast, in France and Germany, the assessment of added benefit is expressed on an ordinal scale, based on an assessment of the clinical outcomes as compared with existing care. This assessment then influences price negotiations. The objective of this paper is to assess the pros and cons of each approach, both in terms of the assessments they produce and the efficiency and practical feasibility of the process. METHODS: We reviewed the technology appraisals performed by the National Institute for Health and Care Excellence (NICE) relating to 49 anticancer drug decisions in the UK from September 2003 to January 2012. Estimates of the QALYs gained and incremental cost per QALY gained were then compared with the assessments of the Amélioration du Service Médical Rendu (ASMR) made by the Haute Autorité de Santé (HAS) in France for the same drugs in the same clinical indications. We also undertook a qualitative assessment of the two approaches, considering the resources required, timeliness, transparency, stakeholder engagement, and political acceptability. RESULTS: In the UK, the estimates of QALYs gained ranged from 0.003 to 1.46 and estimates of incremental cost per QALY from £3,320 to £458,000. The estimate of cost per QALY gained was a good predictor of the level of restriction imposed on the use of the drug concerned. Patient access schemes, which normally imply price reductions, were proposed in 45 % of cases. In France, the distribution of ASMRs was I, 12 %; II, 18 %; III, 24 %; IV, 18 %; V, 22 %; and uncategorized/non-reimbursed, 4 %. Since ASMRs of IV and above signify minor or no improvement over existing therapy, these ratings imply that, in around 40 % of cases, the drugs concerned would face price controls. Overall, the assessments of value added in the two jurisdictions were very similar. A superior ASMR rating was associated with higher QALYs gained. However, a superior ASMR was not associated with a lower incremental cost per QALY. There are substantial differences in respect of the other attributes considered, but these mainly reflect the result of institutional choices in the jurisdictions concerned and it is not possible to conclude that one approach is universally superior to the other. CONCLUSIONS: The two approaches produce very similar assessments of added value, but have different attributes in terms of cost, timeliness, transparency and political acceptability. How these considerations impact market access and prices is difficult to assess, because of the lack of transparency concerning prices in both countries and the fact that market access also depends on a broader range of factors. There is some evidence of convergence in the approaches, with the movement in France towards producing cost-effectiveness estimates and the movement in the UK towards negotiated prices.

Efficacy of duloxetine versus alternative oral therapies: an indirect comparison of randomised clinical trials in chronic low back pain.

INTRODUCTION: The objective of this study was to obtain parameter estimates for the efficacy of duloxetine versus alternative oral therapies for the treatment of chronic low back pain. MATERIALS AND METHODS: Electronic databases were searched to identify randomised, double-blind placebo-controlled trials. Studies reporting pain intensity, with parallel-group design of oral treatments with length of treatment of more than 8 weeks were included. A Bayesian approach to indirect comparisons was applied, using standardised mean difference as a measure of relative treatment effect. RESULTS: Fifteen studies were identified comparing duloxetine with the following oral drug classes: non-scheduled opioids, cyclooxygenase-2 inhibitors, scheduled opioids, selective serotonin reuptake inhibitors, and 'other' (i.e. glucosamine). The primary analysis found scheduled opioids to be more effective than duloxetine for the fixed effects model. However, the estimate of the treatment difference reflected a less than small magnitude of effect (|standardised mean difference| <0.2), and there was no difference for the random effects model. No differences were found in sensitivity analyses involving the subset of patients not receiving concomitant non-steroidal anti-inflammatory medication. CONCLUSION: The available evidence shows that there does not seem to be any difference in efficacy between duloxetine and other oral pharmacological therapies, providing a valuable alternative for this disabling condition.