The Role of Real-World Evidence in UK Reimbursement: Case Study of Lenalidomide in Myelodysplastic Syndrome Deletion 5q.

BACKGROUND: Uncertainty within cost-effectiveness analysis, often driven by lack of mature data from large clinical trials, plays a key role in decisions made by the National Institute for Health and Care Excellence (NICE), particularly for early access medicines and orphan drugs. OBJECTIVES: In this case study, we used real-world evidence to address the uncertainty in the cost-effectiveness case for lenalidomide in transfusion-dependent low- and intermediate-1-risk myelodysplastic syndrome (MDS) deletion 5q [del(5q)], affecting a small but unique subpopulation with an orphan disease. METHODS: As part of a submission to NICE, we developed a cost-effectiveness model for lenalidomide, resulting in eventual recommendation. RESULTS: Due to data limitations within the trial evidence available, the model was based on surrogate outcomes supported by a disease-wide literature review. The validity of modelled estimates for critical long-term outcomes in terms of time on treatment (32% reaching 26 cycles when the patient access scheme applied in the model vs. 28% in the real-world data) and survival was confirmed using real-world evidence (projected median survival for best supportive care of 4.3 years vs. real-world evidence showing median survival with low- and intermediate-1-risk MDS of 5.7 and 3.5 years, respectively). CONCLUSION: This case study demonstrates the usefulness and relevance of the application of real-world data when trial data are limited.

Cost effectiveness of left atrial appendage closure with the Watchman device for atrial fibrillation patients with absolute contraindications to warfarin.

AIMS: Atrial fibrillation (AF) patients with contraindications to oral anticoagulation have had few options for stroke prevention. Recently, a novel oral anticoagulant, apixaban, and percutaneous left atrial appendage closure (LAAC) have emerged as safe and effective therapies for stroke risk reduction in these patients. This analysis assessed the cost effectiveness of LAAC with the Watchman device relative to apixaban and aspirin therapy in patients with non-valvular AF and contraindications to warfarin therapy. METHODS AND RESULTS: A cost-effectiveness model was constructed using data from three studies on stroke prevention in patients with contraindications: the ASAP study evaluating the Watchman device, the ACTIVE A trial of aspirin and clopidogrel, and the AVERROES trial evaluating apixaban. The cost-effectiveness analysis was conducted from a German healthcare payer perspective over a 20-year time horizon. Left atrial appendage closure yielded more quality-adjusted life years (QALYs) than aspirin and apixaban by 2 and 4 years, respectively. At 5 years, LAAC was cost effective compared with aspirin with an incremental cost-effectiveness ratio (ICER) of €16 971. Left atrial appendage closure was cost effective compared with apixaban at 7 years with an ICER of €9040. Left atrial appendage closure was cost saving and more effective than aspirin and apixaban at 8 years and remained so throughout the 20-year time horizon. CONCLUSIONS: This analysis demonstrates that LAAC with the Watchman device is a cost-effective and cost-saving solution for stroke risk reduction in patients with non-valvular AF who are at risk for stroke but have contraindications to warfarin.

A comparison of the cost-effectiveness of treatment of prolonged acute convulsive epileptic seizures in children across Europe.

In the majority of children and adolescents with epilepsy, optimal drug therapy adequately controls their condition. However, among the remaining patients who are still uncontrolled despite mono-, bi- or tri-therapy with chronic anti-epileptic treatment, a rescue medication is required. In Western Europe, the licensed medications available for first-line treatment of prolonged acute convulsive seizures (PACS) vary widely, and so comparators for clinical and economic evaluation are not consistent. No European guidelines currently exist for the treatment of PACS in children and adolescents and limited evidence is available for the effectiveness of treatments in the community setting. The authors present cost-effectiveness data for BUCCOLAM® (midazolam oromucosal solution) for the treatment of PACS in children and adolescents in the context of the treatment pathway in seven European countries in patients from 6 months to 18 years. For each country, the health economic model consisted of a decision tree, with decision nodes informed by clinical data and expert opinion obtained via a Delphi methodology. The events modelled are those associated with a patient experiencing a seizure in the community setting. The model assessed the likelihood of medication being administered successfully and of seizure cessation. The associated resource use was also modelled, and ambulance call-outs and hospitalisations were considered. The patient's quality of life was estimated by clinicians, who completed a five-level EuroQol five dimensions questionnaire from the perspective of a child or adolescent suffering a seizure. Despite differences in current therapy, treatment patterns and healthcare costs in all countries assessed, BUCCOLAM was shown to be cost saving and offered increased health-related benefits for patients in the treatment of PACS compared with the current local standard of care.

A cost-utility analysis of degarelix in the treatment of advanced hormone-dependent prostate cancer in the United Kingdom.

OBJECTIVE: To determine the cost-effectiveness of the treatment of advanced hormone-dependent prostate cancer with degarelix compared to luteinizing hormone-releasing hormone (LHRH) agonists in the UK using the latest available evidence and the model submitted to AWMSG. METHODS: A cost-effectiveness model was developed from the perspective of the UK National Health Service evaluating monthly injection of degarelix against 3-monthly leuprorelin therapy plus anti-androgen flare cover for the first-line treatment of patients with advanced (locally advanced or metastatic) hormone-dependent prostate cancer. A Markov process model was constructed using the patient population characteristics and efficacy information from the CS21 Phase III clinical trial and associated extension study (CS21A). The intention-to-treat (ITT) population and a high-risk sub-group with a PSA level >20 ng/mL were modeled. RESULTS: In the base-case analysis using the patient access scheme (PAS) price, degarelix was dominant compared to leuprorelin with cost savings of £3633 in the ITT population and £4310 in the PSA > 20 ng/mL sub-group. The chance of being cost-effective was 95% in the ITT population and 96% in the PSA > 20 ng/mL sub-group at a threshold of £20,000 per quality-adjusted life-year (QALY). In addition, degarelix remained dominant when PSA progression was assumed equal and only the benefits of preventing testosterone flare were taken into account. Treatment with degarelix also remained dominant in both populations when the list price was used. The additional investment required to treat patients with degarelix could be offset in 19 months for the ITT population and 13 months for the PSA > 20 ng/mL population. The model was most sensitive to the hazard ratio assumed for PSA progression between degarelix and leuprorelin and the quality-of-life (utility) of patients receiving palliative care. CONCLUSION: Degarelix is likely to be cost-effective compared to leuprorelin plus anti-androgen flare cover in the first-line treatment of advanced hormone-dependent prostate cancer.

Cost effectiveness of romiplostim for the treatment of chronic immune thrombocytopenia in Ireland.

BACKGROUND: Romiplostim, a thrombopoietin receptor agonist (TPOra), is a second-line medical treatment option for adults with chronic immune thrombocytopenia (ITP). Clinical trials have shown that romiplostim increases platelet counts, while reducing the risk of bleeding and, in turn, the need for costly rescue medications. AIMS: The objective of this study was to assess the cost effectiveness of romiplostim in the treatment of adult ITP in Ireland, in comparison with eltrombopag and the medical standard of care (SoC). METHODS: A lifetime treatment-sequence cost-utility Markov model with embedded decision tree was developed from an Irish healthcare perspective to compare romiplostim with eltrombopag and SoC. The model was driven by platelet response (platelet count ≥50 × 10(9)/L), which determined effectiveness and progression along the treatment pathway, need for rescue therapy (e.g. intravenous immunoglobulin [IVIg] and steroids) and risk of bleeding. Probability of response, mean treatment duration, average time to initial response and utilities were derived from clinical trials and other published evidence. Treatment sequences and healthcare utilization practice were validated by Irish clinical experts. Costs were assessed in for 2011 and included drug acquisition costs and costs associated with monitoring patients and management of bleeding, as available from published Irish reimbursement lists and other relevant sources. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: Romiplostim treatment resulted in an average of 20.2 fewer administrations of rescue medication (IVIg or intravenous steroids) over a patient lifetime than eltrombopag, and 29.3 fewer rescue medication administrations than SoC. Romiplostim was dominant, with cost savings of 13,258 and 22,673 and gains of 0.76 and 1.17 quality-adjusted life-years (QALYs), compared with eltrombopag and SoC, respectively. Romiplostim remained cost effective throughout a variety of potential scenarios, including short-term TPOra treatment duration (1 year). One-way sensitivity analysis showed that the model was most sensitive to variation in the cost of IVIg and use of romiplostim and IVIg. Probabilistic sensitivity analysis showed that romiplostim was likely to be cost effective in over 90 % of cases compared with eltrombopag, and 96 % compared with SoC at a willingness-to-pay threshold of 30,000 per QALY. CONCLUSIONS: Use of romiplostim in the ITP treatment pathway, compared with eltrombopag or SoC, is likely to be cost effective in Ireland. Romiplostim improves clinical outcomes by increasing platelet counts, reducing bleeding events and the use of IVIg and steroids, resulting in both cost savings and additional QALYs when compared with current treatment practices.

The cost effectiveness of licensed oromucosal midazolam (Buccolam(®)) for the treatment of children experiencing acute epileptic seizures: an approach when trial evidence is limited.

BACKGROUND: In the UK, two treatment options are used for acute epileptic seizures in the community-rectal diazepam and unlicensed buccal midazolam. In practice, the former is rarely used, with unlicensed buccal midazolam being widely recommended and prescribed by physicians. In September 2011, Buccolam(®) (licensed midazolam oromucosal solution) became the first medicine to receive a Paediatric-Use Marketing Authorization (PUMA) and it is indicated for the treatment of prolonged, acute, convulsive seizures by caregivers in the community for children (aged 6 months to <18 years) diagnosed with epilepsy. The approval process for a PUMA product differs from other marketing authorization processes and may be based upon small population subsets and may not, in some cases, require new safety or efficacy data to be generated; a similar situation to that seen for orphan drugs. This can lead to challenges when conducting economic evaluations. OBJECTIVE: The aim of this study was to assess the cost effectiveness of Buccolam(®) for children with a diagnosis of epilepsy suffering prolonged, acute, convulsive seizures occurring in the UK community setting. DESIGN AND PERSPECTIVE: A hybrid model was developed according to a UK payer perspective. The model included a time-to-event simulation for the frequency and location of occurrence of seizures, along with a decision-tree model that assessed the treatment pathway when a seizure occured. The model compared treatment with Buccolam(®) with standard care in the community (95 % unlicensed buccal midazolam and 5 % rectal diazepam) or either treatment alone. The model was informed by data from a variety of sources, including clinical effectiveness estimates, and costs based on published UK data, using 2012-13 prices, where possible. To determine current practice and real-world effectiveness, a Delphi panel and a survey of parents of children with epilepsy were conducted. RESULTS: Buccolam(®) showed a reduction in costs of £2,939 compared with standard care, £14,269 compared with rectal diazepam alone and £886 compared with unlicensed buccal midazolam alone. Increases of 0.025, 0.082 and 0.013 quality-adjusted life-years, respectively, were also seen. Buccolam(®) remained dominant across a range of scenario analyses. CONCLUSION: This model demonstrates the possibility of constructing a thorough economic case when trial or real-world data are not available. The results of the model show Buccolam(®) to be cost saving compared with rectal diazepam due to a reduction in the need for ambulance callouts and hospital stays, and compared with unlicensed buccal midazolam, through reduced drug costs and wastage.

A cost-effectiveness analysis of MMX mesalazine compared with mesalazine in the treatment of mild-to-moderate ulcerative colitis from a UK perspective.

OBJECTIVES: To perform a cost-utility analysis of a new formulation of mesalazine (Mezavant XL, MMX mesalazine) versus an existing oral mesalazine (Asacol; mesalazine) from the UK National Health Service perspective. METHODS: A 5-year Markov cohort model was developed. Costs were obtained from the literature and utilities from an independent study. Uncertainty was evaluated using one-way and probabilistic sensitivity analyses (PSA). The potential effect of dosing frequency on adherence and possible long-term effects of remission maintenance on colorectal cancer (CRC) rates were also investigated. RESULTS: The model suggested that 5-year therapy with MMX mesalazine was likely to generate gains when compared with mesalazine, including a gain of 0.011 QALYs per patient, 19 more remission days, and 12% fewer hospitalizations and surgical episodes. These gains came at an increase in total NHS direct cost of £8, resulting in an incremental cost-effectiveness ratio (ICER) of £749. The PSA suggested that MMX mesalazine had a 62% chance of resulting in cost savings, and a 74% chance of being cost-effective (£20,000 threshold). Extended analysis including adherence and CRC effects suggested further incremental benefit of MMX mesalazine over mesalazine could be expected. Limitations include uncertainty in extrapolation to a 5-year time horizon and impact of adherence and drug acquisition costs on outcomes. CONCLUSION: The pharmacoeconomic analysis suggested that MMX mesalazine is likely to produce small, but worthwhile, increases in total NHS direct cost while increasing time in remission and associated quality of life, when compared with mesalazine. Advantages in adherence to treatment with MMX mesalazine relative to mesalazine suggested that further health gains and cost savings can be obtained. Overall, these results suggest that MMX mesalazine is a cost-effective treatment for UC.