Nasuh Büyükkaramikli

Integrated sensor-augmented pump therapy systems [the MiniMed® Paradigm™ Veo system and the Vibe™ and G4® PLATINUM CGM (continuous glucose monitoring) system] for managing blood glucose levels in type 1 diabetes: a systematic review and economic evaluation

BACKGROUND In recent years, meters for continuous monitoring of interstitial fluid glucose have been introduced to help people with type 1 diabetes mellitus (T1DM) to achieve better control of their disease. OBJECTIVE The objective of this project was to summarise the evidence on the clinical effectiveness and cost-effectiveness of the MiniMed(®) Paradigm™ Veo system (Medtronic Inc., Northridge, CA, USA) and the Vibe™ (Animas(®) Corporation, West Chester, PA, USA) and G4(®) PLATINUM CGM (continuous glucose monitoring) system (Dexcom Inc., San Diego, CA, USA) in comparison with multiple daily insulin injections (MDIs) or continuous subcutaneous insulin infusion (CSII), both with either self-monitoring of blood glucose (SMBG) or CGM, for the management of T1DM in adults and children. DATA SOURCES A systematic review was conducted in accordance with the principles of the Centre for Reviews and Dissemination guidance and the National Institute for Health and Care Excellence Diagnostic Assessment Programme manual. We searched 14 databases, three trial registries and two conference proceedings from study inception up to September 2014. In addition, reference lists of relevant systematic reviews were checked. In the absence of randomised controlled trials directly comparing Veo or an integrated CSII + CGM system, such as Vibe, with comparator interventions, indirect treatment comparisons were performed if possible. METHODS A commercially available cost-effectiveness model, the IMS Centre for Outcomes Research and Effectiveness diabetes model version 8.5 (IMS Health, Danbury, CT, USA), was used for this assessment. This model is an internet-based, interactive simulation model that predicts the long-term health outcomes and costs associated with the management of T1DM and type 2 diabetes. The model consists of 15 submodels designed to simulate diabetes-related complications, non-specific mortality and costs over time. As the model simulates individual patients over time, it updates risk factors and complications to account for disease progression. RESULTS Fifty-four publications resulting from 19 studies were included in the review. Overall, the evidence suggests that the Veo system reduces hypoglycaemic events more than other treatments, without any differences in other outcomes, including glycated haemoglobin (HbA1c) levels. We also found significant results in favour of the integrated CSII + CGM system over MDIs with SMBG with regard to HbA1c levels and quality of life. However, the evidence base was poor. The quality of the included studies was generally low, often with only one study comparing treatments in a specific population at a specific follow-up time. In particular, there was only one study comparing Veo with an integrated CSII + CGM system and only one study comparing Veo with a CSII + SMBG system in a mixed population. Cost-effectiveness analyses indicated that MDI + SMBG is the option most likely to be cost-effective, given the current threshold of £30,000 per quality-adjusted life-year gained, whereas integrated CSII + CGM systems and Veo are dominated and extendedly dominated, respectively, by stand-alone, non-integrated CSII with CGM. Scenario analyses did not alter these conclusions. No cost-effectiveness modelling was conducted for children or pregnant women. CONCLUSIONS The Veo system does appear to be better than the other systems considered at reducing hypoglycaemic events. However, in adults, it is unlikely to be cost-effective. Integrated systems are also generally unlikely to be cost-effective given that stand-alone systems are cheaper and, possibly, no less effective. However, evidence in this regard is generally lacking, in particular for children. Future trials in specific child, adolescent and adult populations should include longer term follow-up and ratings on the European Quality of Life-5 Dimensions scale at various time points with a view to informing improved cost-effectiveness modelling. STUDY REGISTRATION PROSPERO Registration Number CRD42014013764. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Pomalidomide with Dexamethasone for Treating Relapsed and Refractory Multiple Myeloma Previously Treated with Lenalidomide and Bortezomib: An Evidence Review Group Perspective of an NICE Single Technology Appraisal

The National Institute for Health and Care Excellence (NICE), as part of the institute’s single technology appraisal (STA) process, invited the manufacturer of pomalidomide (POM; Imnovid®, Celgene) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with dexamethasone (POM + LoDEX) for the treatment of relapsed and refractory multiple myeloma (RRMM) after at least two regimens including lenalidomide (LEN) and bortezomib (BOR). Kleijnen Systematic Reviews Ltd (KSR) and Erasmus University Rotterdam were commissioned as the Evidence Review Group (ERG) for this submission. The ERG reviewed the evidence submitted by the manufacturer, validated the manufacturer’s decision analytic model, and conducted exploratory analyses in order to assess the robustness and validity of the presented clinical and cost-effectiveness results. This paper describes the company submission, the ERG assessment, and NICE’s subsequent decisions. The company conducted a systematic review to identify studies comparing POM with comparators outlined in the NICE scope: panobinostat with bortezomib and dexamethasone (PANO + BOR + DEX), bendamustine with thalidomide and dexamethasone (BTD) and conventional chemotherapy (CC). The main clinical effectiveness evidence was obtained from MM-003, a randomized controlled trial (RCT) comparing POM + LoDEX with high-dose dexamethasone (HiDEX; used as a proxy for CC). Additional data from other studies were also used as nonrandomized observational data sources for the indirect treatment comparison of POM + LoDEX with BTD and PANO + BOR + DEX. Covariate or treatment switching adjustment methods were used for each comparison. The model developed in Microsoft® Excel 2010 using a semi-Markov partitioned survival structure, submitted in the original submission to NICE for TA338, was adapted for the present assessment of the cost effectiveness of POM + LoDEX. Updated evidence from the clinical-effectiveness part was used for the survival modelling of progression-free survival and overall survival. For POM + LoDEX, the patient access scheme (PAS) discount was applied to the POM price. Three separate comparisons were conducted for each comparator, each comparison using a different dataset and adjustment methods. The ERG identified and corrected some errors, and the corrected incremental cost-effectiveness ratios (ICERs) for POM + LoDEX versus each comparator were presented: approximately £45,000 per quality-adjusted life-year (QALY) gained versus BTD, savings of approximately £143,000 per QALY lost versus PANO + BOR + DEX, and approximately £49,000 per QALY gained versus CC. The ERG also conducted full incremental analyses, which revealed that CC, POM + LoDEX and PANO + BOR + DEX were on the cost-effectiveness frontier. The committee’s decision on the technology under analysis deemed that POM + LoDEX should be recommended as an option for treating multiple myeloma in adults at third or subsequent relapse of treatments including both LEN and BOR, contingent on the company providing POM with the discount agreed in the PAS.

EMA and NICE appraisal processes for cancer drugs : current status and uncertainties

The Evidence Review Group members that contributed to this editorial are funded by the UK NIHR HTA Programme. The views and opinions expressed are those of the authors and do not necessarily reflect those of the UK Department of Health and the NIHR.

Cost-Effectiveness Analysis in Telehealth: A Comparison between Home Telemonitoring, Nurse Telephone Support, and Usual Care in Chronic Heart Failure Management

OBJECTIVES To assess the cost effectiveness of home telemonitoring (HTM) and nurse telephone support (NTS) compared with usual care (UC) in the management of patients with chronic heart failure, from a third-party payers perspective. METHODS We developed a Markov model with a 20-year time horizon to analyze the cost effectiveness using the original study (Trans-European Network-Home-Care Management System) and various data sources. A probabilistic sensitivity analysis was performed to assess the decision uncertainty in our model. RESULTS In the original scenario (which concerned the cost inputs at the time of the original study), HTM and NTS interventions yielded a difference in quality-adjusted life-years (QALYs) gained compared with UC: 2.93 and 3.07, respectively, versus 1.91. An incremental net monetary benefit analysis showed €7,697 and €13,589 in HTM and NTS versus UC at a willingness-to-pay (WTP) threshold of €20,000, and €69,100 and €83,100 at a WTP threshold of €80,000, respectively. The incremental cost-effectiveness ratios were €12,479 for HTM versus UC and €8,270 for NTS versus UC. The current scenario (including telenurse cost inputs in NTS) yielded results that were slightly different from those for the original scenario, when comparing all New York Heart Association (NYHA) classes of severity. NTS dominated HTM, compared with UC, in all NYHA classes except NYHA IV. CONCLUSIONS This modeling study demonstrated that HTM and NTS are viable solutions to support patients with chronic heart failure. NTS is cost-effective in comparison with UC at a WTP of €9000/QALY or higher. Like NTS, HTM improves the survival of patients in all NYHA classes and is cost-effective in comparison with UC at a WTP of €14,000/QALY or higher.

Application of constrained optimization methods in health services research : report 2 of the ISPOR optimization methods emerging good practices task force

BACKGROUND Constrained optimization methods are already widely used in health care to solve problems that represent traditional applications of operations research methods, such as choosing the optimal location for new facilities or making the most efficient use of operating room capacity. OBJECTIVES In this paper we illustrate the potential utility of these methods for finding optimal solutions to problems in health care delivery and policy. To do so, we selected three award-winning papers in health care delivery or policy development, reflecting a range of optimization algorithms. Two of the three papers are reviewed using the ISPOR Constrained Optimization Good Practice Checklist, adapted from the framework presented in the initial Optimization Task Force Report. The first case study illustrates application of linear programming to determine the optimal mix of screening and vaccination strategies for the prevention of cervical cancer. The second case illustrates application of the Markov Decision Process to find the optimal strategy for treating type 2 diabetes patients for hypercholesterolemia using statins. The third paper (described in Appendix 1) is used as an educational tool. The goal is to describe the characteristics of a radiation therapy optimization problem and then invite the reader to formulate the mathematical model for solving it. This example is particularly interesting because it lends itself to a range of possible models, including linear, nonlinear, and mixed-integer programming formulations. From the case studies presented, we hope the reader will develop an appreciation for the wide range of problem types that can be addressed with constrained optimization methods, as well as the variety of methods available. CONCLUSIONS Constrained optimization methods are informative in providing insights to decision makers about optimal target solutions and the magnitude of the loss of benefit or increased costs associated with the ultimate clinical decision or policy choice. Failing to identify a mathematically superior or optimal solution represents a missed opportunity to improve economic efficiency in the delivery of care and clinical outcomes for patients. The ISPOR Optimization Methods Emerging Good Practices Task Forces first report provided an introduction to constrained optimization methods to solve important clinical and health policy problems. This report also outlined the relationship of constrained optimization methods relative to traditional health economic modeling, graphically illustrated a simple formulation, and identified some of the major variants of constrained optimization models, such as linear programming, dynamic programming, integer programming, and stochastic programming. The second report illustrates the application of constrained optimization methods in health care decision making using three case studies. The studies focus on determining optimal screening and vaccination strategies for cervical cancer, optimal statin start times for diabetes, and an educational case to invite the reader to formulate radiation therapy optimization problems. These illustrate a wide range of problem types that can be addressed with constrained optimization methods.

Ribociclib with an Aromatase Inhibitor for Previously Untreated, HR-Positive, HER2-Negative, Locally Advanced or Metastatic Breast Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal

The National Institute for Health and Care Excellence, as part of the institute’s single technology appraisal process, invited the manufacturer of ribociclib (Kisqali®, Novartis) to submit evidence regarding the clinical and cost effectiveness of the drug in combination with an aromatase inhibitor for the treatment of previously untreated, hormone receptor-positive, human epidermal growth factor receptor 2-negative, locally advanced or metastatic breast cancer. Kleijnen Systematic Reviews Ltd and Erasmus University Rotterdam were commissioned as the Evidence Review Group for this submission. The Evidence Review Group reviewed the evidence submitted by the manufacturer, corrected and validated the manufacturer’s decision analytic model, and conducted exploratory analyses to assess the robustness and validity of the presented clinical and cost-effectiveness results. This article describes the company submission, the Evidence Review Group assessment and National Institute for Health and Care Excellence subsequent decisions. The main clinical effectiveness evidence was obtained from the MONALEESA-2 trial, a randomised controlled trial comparing ribociclib plus letrozole with placebo plus letrozole. Progression-free survival was significantly longer in the ribociclib group (95% confidence interval, 19.3–not reached) vs. 14.7 months (95% confidence interval 13.0–16.5) in the placebo group. To assess the cost effectiveness of ribociclib in combination with an aromatase inhibitor, the company developed an individual patient-level model using a discrete-event simulation approach in Microsoft® Excel. In the model, simulated patients move through a series of three health states until death, i.e. first-line progression-free survival, second-line progression-free survival and progressive disease. The length of progression-free survival during the first line was informed by the MONALEESA-2 trial. The benefit in progression-free survival in the first line was transferred to a benefit in overall survival assuming full progression-free survival to overall survival surrogacy (because of the immaturity of overall survival data from the MONALEESA-2 trial). Patient-level data from the BOLERO-2 trial, evaluating the addition of everolimus to exemestane in the second-line treatment of postmenopausal HR-positive advanced breast cancer, were used to inform the length of progression-free survival during the second line. Costs included in the model were treatment costs (e.g. technology acquisition costs of first, second, third and/or later line treatments), drug administration costs, monitoring costs and health state costs (including terminal care). Additionally, the costs of adverse events associated with the first-line treatment were incorporated. The Evidence Review Group recalculated the incremental cost-effectiveness ratio using data from a different data cut-off date from the MONALEESA-2 trial and by changing some assumptions (e.g. progression-free survival to overall survival surrogacy approach and post-progression third and/or later line treatment-related costs). After two appraisal committee meetings and a revised base case submitted by the company (including a second enhanced patient access scheme discount), the committee concluded that taking into account the uncertainties in the calculation of the cost effectiveness, there were plausible cost-effectiveness estimates broadly in the range that could be considered as a cost-effective use of National Health Service resources. Therefore, ribociclib was recommended as a treatment option for the first-line treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, contingent on the company providing ribociclib with the discount agreed in the second enhanced patient access scheme.