Robert Hettle

Systematic literature review and network meta-analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing–remitting multiple sclerosis

Abstract Objective: To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing–remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA + DAT), using systematic literature review (SLR) and network meta-analysis (NMA). Methods: MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA) and safety. Results: Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < .05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < .05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA + DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs. Conclusion: In this first NMA to consider cladribine tablets, ocrelizumab and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA + DAT populations.

Challenges in economic modeling of anticancer therapies: an example of modeling the survival benefit of olaparib maintenance therapy for patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer

Abstract Objective: The aim of this paper is to describe a four health-state, semi-Markov model structure with health states defined by initiation of subsequent treatment, designed to make best possible use of the data available from a phase 2 clinical trial. Method: The approach is illustrated using data from a sub-group of patients enrolled in a phase 2 clinical trial of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (NCT00753545). A semi-Markov model was developed with four health states: progression-free survival (PFS), first subsequent treatment (FST), second subsequent treatment (SST), and death. Transition probabilities were estimated by fitting survival curves to trial data for time from randomization to FST, time from FST to SST, and time from SST to death. Results: Survival projections generated by the model are broadly consistent with the outcomes observed in the clinical trial. However, limitations of the trial data (small sample size, immaturity of the PFS and overall survival [OS] end-points, and treatment switching) create uncertainty in estimates of survival. Conclusion: The model framework offers a promising approach to evaluating cost-effectiveness of a maintenance therapy for patients with cancer, which may be generalizable to other chronic diseases.

Cost-effectiveness of cladribine tablets, alemtuzumab, and natalizumab in the treatment of relapsing-remitting multiple sclerosis with high disease activity in England

Abstract Aims: Cladribine tablets were the first oral short-course treatment approved for highly active relapsing multiple sclerosis (MS). The Association of British Neurologists guidelines currently recommend two infusion therapies, alemtuzumab and natalizumab, to treat high disease activity relapsing remitting MS (HDA-RRMS). This analysis assessed the cost-effectiveness of cladribine tablets in HDA-RRMS compared with alemtuzumab and natalizumab, from the perspective of the National Health Service (NHS) in England. Materials and methods: A cohort-based Markov model with 11 health states (10 Expanded Disability Status Scale [EDSS] plus death) was developed. Transition matrices from the British Columbia registry were used to model the natural history of EDSS. The treatment effect on EDSS was modelled using hazard ratios for 6-month confirmed disability progression from an indirect treatment comparison (ITC). Relapses and drug-related adverse events were modeled via annualized relapse rates and event probabilities, with associated costs and quality-adjusted life year (QALY) losses. Utilities were derived from trials and the literature, and costs from NHS and literature sources. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses. Results: Cladribine tablets were dominant (i.e., less costly and more effective) vs alemtuzumab and natalizumab in pairwise comparisons, and the dominant strategy in fully incremental analyses. Incremental cost was driven largely by drug acquisition and administration costs, and incremental QALY gain largely by differences in delayed EDSS progression. Cladribine tablets had a 93% probability of being cost-effective at a threshold of GBP 30,000 per QALY gained, and remained dominant across the scenario analyses tested. The greatest influence on results was the treatment effect on disability progression derived from the ITC. Limitations: Uncertainty over the efficacy of DMT beyond trial durations. In line with other comparative effectiveness analyses, the network meta-analysis informing this cost-effectiveness analysis was associated with a degree of uncertainty. No treatment switching analyses were undertaken. Conclusions: Cladribine tablets are a cost-effective alternative to alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the NHS in England.

Cost-effectiveness of bedaquiline in MDR and XDR tuberculosis in Italy

ABSTRACT Objective: To evaluate the cost-effectiveness of bedaquiline plus background drug regimens (BR) for multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) in Italy. Methods: A Markov model was adapted to the Italian setting to estimate the incremental cost-effectiveness ratio (ICER) of bedaquiline plus BR (BBR) versus BR in the treatment of MDR-TB and XDR-TB over 10 years, from both the National Health Service (NHS) and societal perspective. Cost-effectiveness was evaluated in terms of life-years gained (LYG). Clinical data were sourced from trials; resource consumption for compared treatments was modelled according to advice from an expert clinicians panel. NHS tariffs for inpatient and outpatient resource consumption were retrieved from published Italian sources. Drug costs were provided by reference centres for disease treatment in Italy. A 3% annual discount was applied to both cost and effectiveness. Deterministic and probabilistic sensitivity analyses were conducted. Results: Over 10 years, BBR vs. BR alone is cost-effective, with ICERs of €16,639/LYG and €4081/LYG for the NHS and society, respectively. The sensitivity analyses confirmed the robustness of the results from both considered perspectives. Conclusion: In Italy, BBR vs. BR alone has proven to be cost-effective in the treatment of MDR-TB and XDR-TB under a range of scenarios.

Cost-effectiveness of pembrolizumab versus brentuximab vedotin for patients with relapsed or refractory classical Hodgkin’s lymphoma: a United States payer perspective

Abstract Aims: Patients with classical Hodgkin’s lymphoma (cHL) who have relapsed after or are ineligible for autologous stem cell transplantation (ASCT) have limited treatment options and generally a poor prognosis. Pembrolizumab was recently approved in the US for the treatment of such patients having demonstrated clinical benefit and tolerability in relapsed/refractory cHL; however, the cost-effectiveness of pembrolizumab in this population is currently unknown. Materials and methods: A three-state Markov model (progression-free [PF], progressed disease, and death) was developed to assess the cost-effectiveness of pembrolizumab (200 mg) vs brentuximab vedotin (BV; 1.8 mg/kg) in patients with relapsed/refractory cHL after ASCT who have not received BV post-ASCT over a 20-year time horizon from a US payer perspective. PF survival was modeled using a naïve indirect treatment comparison of data from KEYNOTE-087 and the SG035-003 trial. Post-progression survival was modeled using data from published literature. Costs (drug acquisition and administration, disease management, subsequent treatment, and adverse events) and outcomes were discounted at an annual rate of 3.0%. Uncertainty surrounding cost-effectiveness was assessed via probabilistic, deterministic, and scenario analyses. Results: In the base case, pembrolizumab was predicted to yield an additional 0.574 life-years (LYs) and 0.500 quality-adjusted life-years (QALYs) vs BV and cost savings of

Budget impact of including ribociclib in combination with letrozole on US payer formulary: first-line treatment of post-menopausal women with HR+/HER2− advanced or metastatic breast cancer

63,278. Drug acquisition costs were the biggest driver of incremental costs between strategies. Pembrolizumab had a 99.6% probability of being cost-effective compared with BV at a willingness-to-pay threshold of

Cost-Effectiveness of Ribociclib Plus Letrozole Versus Palbociclib Plus Letrozole for Postmenopausal Women with Hormone Receptor-Positive (HR+), Human Epidermal Growth Factor Receptor 2-Negative (HER2–) Advanced/Metastatic Breast Cancer from A UK National Health Service Perspective

20,000/QALY and dominated BV in all scenarios tested. Limitations: The analysis was subject to potential bias due to the use of a naïve indirect treatment comparison and, given the current immaturity of OS in KEYNOTE-087, PPS was assumed equivalent across both treatments. Conclusion: Pembrolizumab is a cost-effective alternative to BV for patients with relapsed/refractory cHL after ASCT.

Budget Impact of Ribociclib Plus Letrozole For The Treatment of Post-Menopausal Women With Hormone Receptor-Positive (HR+), Human Epidermal Growth Factor Receptor 2- Negative (HER2-) Advanced or Metastatic Breast Cancer From A US Private Third-Party Payer Perspective

Abstract Objectives: The combination of a cyclin-dependent kinase 4 and 6 (CDK 4/6) inhibitor with the aromatase inhibitor letrozole is a safe and effective alternative to letrozole monotherapy for first-line hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. This study evaluates the budget impact of using the CDK 4/6 inhibitor ribociclib plus letrozole as a first-line treatment option for postmenopausal women with HR+/HER2− advanced breast cancer, from a United States (US) payer perspective. Methods: A cohort-based budget impact model was used to calculate the incremental cost of introducing ribociclib plus letrozole over three years for the target population. The analysis compared two scenarios: treatment options excluding or including ribociclib plus letrozole. Market shares were derived from market research and the assumption was the introduction of ribociclib plus letrozole would only displace existing CDK-based therapies. Treatment duration was based on the median time to treatment discontinuation or median progression-free survival for first-line treatment, and on clinical trial data for second- and third-line treatment. Acquisition costs were based on wholesale acquisition costs and considered co-payment. Costs for drug administration and monitoring, subsequent therapy, and relevant adverse events were included. Results: Of 1 million insured members, 263 were eligible for CDK 4/6 inhibitor treatment. Cumulative total savings with ribociclib plus letrozole were

Cost Effectiveness of Ribociclib Plus Letrozole Versus Palbociclib Plus Letrozole for The Treatment of Post-Menopausal Women with Hormone Receptor-Positive (HR+), Human Epidermal Growth Factor Receptor 2-Negative (HER2-) Advanced or Metastatic Breast Cancer from A US Private Third-Party Payer Perspective

3.01M over three years, corresponding to a cumulative incremental cost saving of

Health State Utilities In Patients with Relapsing Remitting Multiple Sclerosis Treated with Cladribine Tablets

318.11 per member treated per month. Conclusions: In the US, ribociclib plus letrozole represents a cost-saving first-line treatment option for postmenopausal women with HR+/HER2− advanced breast cancer.