Patient-reported outcome measures for systemic lupus erythematosus clinical trials: a review of content validity, face validity and psychometric performance.

BACKGROUND: Despite overall progress in treatment of autoimmune diseases, patients with systemic lupus erythematosus (SLE) experience many inflammatory symptoms representing an unmet medical need. This study aimed to create a conceptual model of the humanistic and economic burden of SLE, and review the patient-reported outcomes (PROs) used to measure such concepts in SLE clinical trials. METHODS: A conceptual model for SLE was developed from structured review of published articles from 2007 to August 2013 identified from literature databases (MEDLINE, EMBASE, PsycINFO, EconLit) plus other sources (PROLabels, FDA/EMA websites, Clinicaltrials.gov). PROs targeting key symptoms/impacts were identified from the literature. They were reviewed in the context of available guidance and assessed for face and content validity and psychometric properties to determine appropriateness for use in SLE trials. RESULTS: The conceptual model identified fatigue, pain, cognition, daily activities, emotional well-being, physical/social functioning and work productivity as key SLE concepts. Of the 68 articles reviewed, 38 reported PRO data. From these and the other sources, 15 PROs were selected for review, including SLE-specific health-related quality of life (HRQoL) measures (n = 5), work productivity (n = 1), and generic measures of fatigue (n = 3), pain (n = 2), depression (n = 2) and HRQoL (n = 2). The Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue), Brief Pain Inventory (BPI-SF) and LupusQoL demonstrated the strongest face validity, conceptual coverage and psychometric properties measuring key concepts in the conceptual model. All PROs reviewed, except for three Lupus-specific measures, lacked qualitative SLE patient involvement during development. The Hospital Anxiety and Depression Scale (HADS), Short Form [36 item] Health Survey version 2 (SF-36v2), EuroQoL 5-dimensions (EQ-5D-3L and EQ-5D-5L) and Work Productivity and Activity Impairment Questionnaire: Lupus (WPAI:Lupus) showed suitability for SLE economic models. CONCLUSIONS: Based on the identification of key symptoms and impacts of SLE using a scientifically sound conceptual model, we conclude that SLE is a condition associated with high unmet need and considerable burden to patients. This review highlights the availability and need for disease-specific and generic patient-reported measures of relevant domains of disease signs and symptoms, HRQoL and work productivity, providing useful insight for SLE clinical trial design.

Evaluation of the Clinical and Economic Burden of Poor Glycemic Control Associated with Therapeutic Inertia in Patients with Type 2 Diabetes in the United States.

INTRODUCTION: Therapeutic inertia refers to the failure to initiate or intensify treatment in a timely manner and is widespread in type 2 diabetes (T2D) despite the well-established importance of maintaining good glycemic control. The aim of this analysis was to quantify the clinical and economic burden associated with poor glycemic control due to therapeutic inertia in patients with T2D in the USA. METHODS: The IQVIA CORE Diabetes Model was used to simulate life expectancy, costs associated with diabetes-related complications, and lost workplace productivity in US patients. Baseline glycated hemoglobin (HbA1c) levels were 7.0% (53 mmol/mol), 9.0% (75 mmol/mol), 11.0% (97 mmol/mol) 13.0% (119 mmol/mol), or 15.0% (140 mmol/mol), with targets of 6.5% (48 mmol/mol), 7.0% (53 mmol/mol), 8.0% (64 mmol/mol), or 9.0% (75 mmol/mol) depending on baseline HbA1c, across several delayed intensification scenarios (values above target were defined as poor control). The burden associated with intensification delays of 1, 2, 3, 5, and 7 years was estimated over time horizons of 1-30 years. Future costs and clinical benefits were discounted at 3% annually. RESULTS: In a population of 13.4 million patients with T2D and baseline HbA1c of 9.0% (75 mmol/mol), delaying intensification of therapy by 1 year was associated with a loss of approximately 13,390 life-years and increased total costs of US dollars (USD) 7.3 billion (1-year time horizon). Longer delays in intensification were associated with a greater economic burden. Delaying intensification by 7 years was projected to cost approximately 3 million life-years and USD 223 billion over a 30-year time horizon. CONCLUSION: Therapeutic inertia is common in routine clinical practice and makes a substantial contribution to the burden associated with type 2 diabetes in the USA. Initiatives and interventions aimed at preventing therapeutic inertia are needed to improve clinical outcomes and avoid excess costs.

Orally Administered Semaglutide Versus GLP-1 RAs in Patients with Type 2 Diabetes Previously Receiving 1-2 Oral Antidiabetics: Systematic Review and Network Meta-Analysis.

INTRODUCTION: Orally administered semaglutide is the first glucagon-like peptide 1 receptor agonist (GLP-1 RA) for oral administration. As head-to-head trials assessing orally administered semaglutide as an add-on to 1-2 oral antidiabetic drugs (OADs) vs other GLP-1 RAs are limited, a network meta-analysis (NMA) was performed to assess the relative efficacy and safety of orally administered semaglutide 14 mg once-daily (QD) vs injectable GLP-1 RAs in patients with type 2 diabetes inadequately controlled on 1-2 OADs. METHODS: A systematic literature review was conducted to identify randomised controlled trials of GLP-1 RAs in patients inadequately controlled on 1-2 OADs. Data at 26 ± 4 weeks were extracted for efficacy and safety outcomes feasible for the NMA: change from baseline in glycated haemoglobin (HbA1c), weight, HbA1c target levels (< 7.0% and ≤ 6.5%), blood pressure, and any gastrointestinal adverse events specified in system organ class. Data were synthesised using NMA and a Bayesian framework. RESULTS: In total, 27 studies were included in the analyses. Orally administered semaglutide 14 mg QD was associated with significantly greater reductions in HbA1c vs most comparators, and numerically greater reductions vs semaglutide 0.5 mg once-weekly (QW), dulaglutide 1.5 mg QW and liraglutide 1.8 mg QD. HbA1c reductions with semaglutide 1 mg QW were numerically greater than those with orally administered semaglutide 14 mg QD. Reductions in body weight for orally administered semaglutide 14 mg QD were significantly greater than all comparators except semaglutide QW (both doses). Orally administered semaglutide QD 14 mg was associated with statistically similar odds of experiencing gastrointestinal adverse events vs injectable GLP-1 RAs. CONCLUSION: Orally administered semaglutide 14 mg QD as an add-on to 1-2 OADs is one of the most efficacious GLP-1 RAs for reducing HbA1c and body weight at 26 ± 4 weeks. Orally administered semaglutide 14 mg QD is well tolerated, with a safety profile in line with the GLP-1 RA class. FUNDING: Novo Nordisk.

Cost-Effectiveness of Insulin Degludec/Insulin Aspart Versus Biphasic Insulin Aspart in Patients with Type 2 Diabetes from a Danish Health-Care Perspective.

INTRODUCTION: To evaluate the cost-effectiveness of the co-formulation insulin degludec/insulin aspart (IDegAsp) versus biphasic insulin aspart (BIAsp 30), both administered twice daily, in patients with type 2 diabetes mellitus (T2DM), using a short-term cost-effectiveness model. METHODS: Data from two phase 3a treat-to-target clinical trials were used to populate a simple and transparent short-term cost-effectiveness model. The costs and effects of treatment with IDegAsp versus BIAsp 30 were calculated over a 5-year period, from a Danish health-care cost perspective. One-way and probabilistic sensitivity analyses were conducted to assess the degree of uncertainty and robustness of the results. RESULTS: The base-case incremental cost-effectiveness ratio (ICER) of 81,507.91 Danish Kroner (DKK) per quality-adjusted life year (QALY) demonstrates that IDegAsp is a cost-effective treatment compared with BIAsp 30, over a 5-year time horizon. One-way sensitivity analyses show that the ICERs remain within an acceptable range when the rates of hypoglycemia, unit cost of hypoglycemia, disutilities of hypoglycemic events, and the time horizon are varied, ranging from 71,012 DKK to 209,446 DKK. The probabilistic sensitivity analysis demonstrates that the probability that IDegAsp is cost-effective relative to BIAsp 30 is 99.50%, assuming a cost-effectiveness threshold of 250,000 DKK per QALY. CONCLUSION: This short-term cost-effectiveness model shows that IDegAsp is a cost-effective treatment compared with BIAsp 30 for patients with T2DM. This result is primarily driven by significant reductions in severe hypoglycemia and insulin dose observed with IDegAsp versus BIAsp 30. Sensitivity analyses demonstrate the robustness of these results. FUNDING: Novo Nordisk A/S, Søborg, Denmark.

The Economic and Health-related Impact of Crohn's Disease in the United States: Evidence from a Nationally Representative Survey.

BACKGROUND: Approximately 593,000 to 780,000 people in the United States (US) have been diagnosed with Crohn's disease (CD), and an additional 33,000 are diagnosed yearly. Our objective was to estimate CD's impact on medical costs, lost earnings, work and school absences, health status, and health-related quality of life (HRQOL) in the US and to compute current and forecasted national costs. METHODS: We used the nationally representative Medical Expenditure Panel Survey to match 539 respondents with CD to similar respondents without any inflammatory bowel disease (IBD). We estimated annual costs, work and school absences, and self-assessed health status. HRQOL was assessed by the SF-12 Physical Component Summary and Mental Component Summary (PCS and MCS) scores. CD prevalence rates, population counts, and costs were used to forecast total national costs. RESULTS: CD is associated with higher medical costs ($13,446 versus $6029) and lost earnings ($1249 versus $644) and is responsible for $3.48 billion in total national costs (expected to increase to $3.72 billion in 2025). Respondents with CD were more likely to miss work (38% versus 33%) or school (64% versus 33%), less likely to report being in excellent or very good physical health (24% versus 63%), and experienced lower HRQOL measured by the Physical Component Summary (43.4 versus 48.5) and Mental Component Summary (48.6 versus 50.0) than those without IBD. CONCLUSIONS: CD is responsible for increased medical care costs and lower earnings, health status, and HRQOL. These data can serve as benchmarks when examining future CD-related costs and HRQOL.

Key data elements for use in cost-utility modeling of biological treatments for rheumatoid arthritis.

OBJECTIVES: Economic evaluation is becoming more common and important as new biologic therapies for rheumatoid arthritis (RA) are developed. While much has been published about how to design cost-utility models for RA to conduct these evaluations, less has been written about the sources of data populating those models. The goal is to review the literature and to provide recommendations for future data collection efforts. METHODS: This study reviewed RA cost-utility models published between January 2006 and February 2014 focusing on five key sources of data (health-related quality-of-life and utility, clinical outcomes, disease progression, course of treatment, and healthcare resource use and costs). It provided recommendations for collecting the appropriate data during clinical and other studies to support modeling of biologic treatments for RA. RESULTS: Twenty-four publications met the selection criteria. Almost all used two steps to convert clinical outcomes data to utilities rather than more direct methods; most did not use clinical outcomes measures that captured absolute levels of disease activity and physical functioning; one-third of them, in contrast with clinical reality, assumed zero disease progression for biologic-treated patients; little more than half evaluated courses of treatment reflecting guideline-based or actual clinical care; and healthcare resource use and cost data were often incomplete. CONCLUSIONS: Based on these findings, it is recommended that future studies collect clinical outcomes and health-related quality-of-life data using appropriate instruments that can convert directly to utilities; collect data on actual disease progression; be designed to capture real-world courses of treatment; and collect detailed data on a wide range of healthcare resources and costs.

Efficacy and Safety of Anti-Interleukin-20 Monoclonal Antibody in Patients With Rheumatoid Arthritis: A Randomized Phase IIa Trial.

OBJECTIVE: Interleukin-20 (IL-20) is implicated in the pathogenesis of rheumatoid arthritis (RA). The efficacy, safety, and tolerability of NNC0109-0012, a selective anti-IL-20 recombinant human monoclonal antibody (mAb), were assessed in patients with active RA who had an inadequate response to methotrexate therapy. METHODS: Sixty-seven patients with RA were enrolled and randomized (2:1) to receive NNC0109-0012 (3 mg/kg per week, subcutaneously) or placebo in a phase IIa, double-blind, 12-week trial with a 13-week followup. The primary end point was change in the Disease Activity Score in 28 joints based on C-reactive protein level (DAS28-CRP) from baseline to week 12. RESULTS: In patients treated with NNC0109-0012, the primary end point, improvement in the DAS28-CRP at week 12, was achieved (estimated difference -0.88; P = 0.02), with significant improvement starting at week 1. A greater response was observed in seropositive patients (estimated difference -1.66; P < 0.001), which was sustained through 13 weeks of followup, whereas no improvement was noted in patients with seronegative RA. A significant proportion of patients with seropositive RA receiving NNC0109-0012, compared to those receiving placebo, achieved treatment responses according to the American College of Rheumatology 20% (ACR20) (59% versus 21%), ACR50 (48% versus 14%), and ACR70 (35% versus 0%) levels of improvement, and showed greater improvements in the Health Assessment Questionnaire disability index (P = 0.047). The most frequent adverse events reported with NNC0109-0012 were injection site reactions and infections (e.g., herpes, nasopharyngitis, respiratory, and urinary). No serious infections or discontinuations associated with NNC0109-0012 were observed. CONCLUSION: In this phase IIa trial, treatment with NNC0109-0012 (anti-IL-20 mAb) was effective in patients with seropositive RA as early as week 1, with further improvements to week 12. No safety or tolerability concerns were identified with weekly NNC0109-0012 administration.

Development of a conceptual model evaluating the humanistic and economic burden of Crohn's disease: implications for patient-reported outcomes measurement and economic evaluation.

The primary objective of this review is to develop a conceptual model for Crohn's disease (CD) outlining the disease burden for patients, healthcare systems and wider society, as reported in the scientific literature. A search was conducted using MEDLINE, PsycINFO, EconLit, Health Economic Evaluation Database and Centre for Reviews and Dissemination databases. Patient-reported outcome (PRO) measures widely used in CD were reviewed according to the US FDA PRO Guidance for Industry. The resulting conceptual model highlights the characterization of CD by gastrointestinal disturbances, extra-intestinal and systemic symptoms. These symptoms impact physical functioning, ability to complete daily activities, emotional wellbeing, social functioning, sexual functioning and ability to work. Gaps in conceptual coverage and evidence of reliability and validity for some PRO measures were noted. Review findings also highlight the substantial direct and indirect costs associated with CD. Evidence from the literature confirms the substantial burden of CD to patients and wider society; however, future research is still needed to further understand burden from the perspective of patients and to accurately understand the economic burden of disease. Challenges with existing PRO measures also suggest the need for future research to refine or develop new measures.

[Costs of biological treatment of rheumatoid arthritis]. / Omkostninger til biologisk behandling af leddegigt.

INTRODUCTION: Biological drugs are used for the treatment of severe rheumatoid arthritis (RA). The high costs of such treatment have drawn attention to the economic appropriateness of the use of biological drugs. There are no Danish studies of the real costs of present clinical practice. The purpose of this study was to compare the actual costs of RA treatment for the three most commonly used biological drugs. MATERIAL AND METHODS: Data were collected from three Danish hospitals. The study is a cost analysis designed as a retrospective cohort study using data from medical records (n = 198). RESULTS: The costs of infliximab varied due to dose escalation from 78,660 DKK at one hospital to 120,657 DKK at another hospital. Treatment with either etanercept or adalimumab will tend to cost the same as or less than treatment with infliximab, when infliximab doses exceed the standard dose (3 mg/kg), and treatment breaks amount to at least 10%. At one hospital treatment breaks reduced the consumption of etanercept and adalimumab by 20%. CONCLUSION: Actual medicine expenses for treatment of RA with infliximab, etanercept and adalimumab tend to be equal. Consequently, there is no economic rationale for basing the choice of drug on costs calculated on the basis of standard dosage. Instead, the choice should be based on considerations of efficacy, safety, patient needs and the treatment feasibility.

Cost-effectiveness of budesonide/formoterol for maintenance and reliever asthma therapy in Denmark--cost-effectiveness analysis based on five randomised controlled trials.

BACKGROUND AND AIMS: Budesonide/formoterol maintenance and reliever therapy (Symbicort SMART) is an effective asthma-management regime where patients use budesonide/formoterol both as maintenance treatment and as additional doses as needed to improve overall asthma control by reducing symptoms and exacerbations. The aim of this study was to determine the cost-effectiveness of the Symbicort SMART regime in Denmark vs higher dose inhaled corticosteroid (ICS) plus reliever medication, similar dose inhaled corticosteroid/long-acting beta(2)-agonist (ICS/LABA) combination therapy plus reliever medication or higher dose of inhaled ICS/LABA combination therapy plus reliever medication. METHODS: The cost-effectiveness analyses were based on effectiveness and resource utilisation data, which were prospectively collected during the treatment period in five randomised clinical trials (duration: 24 weeks, 26 weeks or 1 year). Economic analyses were conducted from both a health care sector (direct costs) and a societal perspective [total costs, i.e direct costs + indirect costs (sick leave)]. The time horizon for the economic analyses was 1 year. The effectiveness measure used was the number of avoided severe exacerbations per patient per year. RESULTS: Patients treated with budesonide/formoterol maintenance and reliever therapy showed statistically significant fewer severe exacerbations per patient compared with the alternative treatment regimes in all comparisons. Budesonide/formoterol maintenance and reliever therapy was a dominant treatment option when compared with higher dose ICS or higher dose ICS/LABA, i.e. it was more effective at a lower total cost. In two of the three comparisons with a similar ICS/LABA dose, Symbicort SMART was dominant. CONCLUSION: Cost-effectiveness analyses of budesonide/formoterol maintenance and reliever therapy show that the significant reduction in the number of severe exacerbations observed in all the included clinical studies is predominately obtained at lower costs compared with alternative treatment regimes. This indicates that budesonide/formoterol maintenance and reliever therapy is a cost-effective treatment option in a Danish setting.