De Novo Cost-Effectiveness Model Framework for Nonalcoholic Steatohepatitis-Modeling Approach and Validation.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with hepatic morbidity and mortality and extra-hepatic comorbidities. Published NASH cost-effectiveness models (CEMs) are heterogeneous and consistently omit comorbid conditions that frequently co-exist alongside NASH. We aimed to develop a de novo CEM framework that incorporates extra-hepatic disease states and outcomes alongside hepatic components to enable future estimation of the cost-effectiveness of NASH interventions. METHODS: Patient-level simulation and cohort-level Markov models were implemented in the same framework. Model inputs included fibrosis progression; late-stage liver disease outcomes; comorbidity outcomes for cardiovascular disease, type 2 diabetes, and obesity; mortality; health-related quality of life; and direct medical costs. The prototype analysis assessed the cost-effectiveness of obeticholic acid versus standard of care from a US payer perspective over a lifetime horizon with costs and effects discounted at 3% per annum. However, the CEM was designed for easy adaptation to other countries, time horizons, and other considerations. Efficacy and adverse event parameters were obtained from the 18-month interim analysis of the REGENERATE trial. Outputs include total and incremental costs, total life years, and quality-adjusted life years. RESULTS: In this model, total costs, total life years, and quality-adjusted life years were all higher with obeticholic acid compared with standard of care. Cross-validation of this model with the 2016 and 2020 Institute for Clinical and Economic Review models revealed marked differences, mainly driven by mortality inputs, transition probability estimates, and incorporation of the effect of treatment and comorbidities. CONCLUSION: This is the first CEM in NASH to incorporate the clinical consequences of several comorbidities. The flexible yet standardized framework permits estimation of the cost-effectiveness of NASH interventions in a variety of settings. The model currently includes several assumptions and will be further developed as more relevant data become available.

Mid-fidelity manikins improve first-year pharmacy students' confidence and accuracy with performing physical assessment.

INTRODUCTION: As clinical roles for pharmacists expand, effective physical assessment training for pharmacy students is essential. The study objective was to determine whether doctor of pharmacy students taught physical assessment using mid-fidelity manikins improved in confidence and accuracy. Long-term retention of skills was also measured. METHODS: First-year (P1) pharmacy students were enrolled in a case-based course over two semesters between August 2018 and May 2019. Manikins were incorporated into the fall semester course for students to perform physical assessment as part of the individual case workup process. Students completed surveys before and after the course to evaluate differences in their confidence and accuracy with detecting normal vs. abnormal vital signs. After 21 weeks of no manikin exposure, students were again surveyed and assessed to evaluate long-term retention of physical assessment skills. RESULTS: Fifty-six students were included. Student confidence in assessing heart rate, blood pressure (BP), and lung sounds improved significantly between pre-exposure and post-exposure (34%, 39%, and 71% improvement, respectively), and accuracy in assessing BP and lung sounds improved significantly between pre-exposure and post-exposure (28% and 23% improvement, respectively). Confidence and accuracy were maintained throughout the study including follow-up. CONCLUSIONS: Early introduction of mid-fidelity manikins to P1 pharmacy students in a case-based, spaced learning strategy provided a successful approach to teach physical assessment skills.

Modeling long-term health and economic implications of new treatment strategies for Parkinson's disease: an individual patient simulation study.

Background: Simulation modeling facilitates the estimation of long-term health and economic outcomes to inform healthcare decision-making. Objective: To develop a framework to simulate progression of Parkinson's disease (PD), capturing motor and non-motor symptoms, clinical outcomes, and associated costs over a lifetime. Methods: A patient-level simulation was implemented accounting for individual variability and interrelated changes in common disease progression scales. Predictive equations were developed to model progression for newly diagnosed patients and were combined with additional sources to inform long-term progression. Analyses compared a hypothetical disease-modifying therapy (DMT) with a standard of care to explore the drivers of cost-effectiveness. Results: The equations captured the dependence between the various measures, leveraging prior values and rates of change to obtain realistic predictions. The simulation was built upon several interrelated equations, validated by comparison with observed values for the Movement Disorder Society Unified PD Rating Scale (MDS-UPDRS) and UPDRS subscales over time. In a case study, disease progression rates, patient utilities, and direct non-medical costs were drivers of cost-effectiveness. Conclusions: The developed equations supported the simulation of early PD. This model can support conducting simulations to inform internal decision-making, trial design, and strategic planning early in the development of new DMTs entering clinical trials.

The cost-effectiveness of dacomitinib in first-line treatment of advanced/metastatic epidermal growth factor receptor mutation-positive non-small-cell lung cancer (EGFRm NSCLC) in Sweden.

AIMS: Although the benefit of first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) over chemotherapy in EGFR mutation-positive (EGFRm) non-small-cell lung cancer (NSCLC) has been demonstrated in clinical trials, the optimal treatment sequence remains unclear. The objective of our study was to evaluate the cost-effectiveness of dacomitinib in Sweden vs afatinib and osimertinib in first-line treatment of EGFRm NSCLC. MATERIALS AND METHODS: A partitioned survival model was developed with three health states: progression-free, post-progression, and death. Progression-free and overall survival curves were used to inform movements between states. Clinical data were taken from randomized trials, compared via a network meta-analysis (NMA). Utility data were taken from published studies and costs from national Swedish sources. The model used a 15-year time horizon and a Swedish healthcare payer perspective. Sensitivity and scenario analyses were performed. RESULTS: The base-case analysis showed that dacomitinib accrued a total of 2.10 quality-adjusted life-years (QALYs) at a total cost of Swedish krona (SEK) 874,615. The incremental cost-effectiveness ratio (ICER) for dacomitinib vs afatinib was SEK 461,556 per QALY gained. The ICER of osimertinib vs dacomitinib, where the small QALY gains of the former came at a high additional cost, was SEK 11,444,709. Deterministic and probabilistic sensitivity analyses confirmed the robustness of these results; changes to drug and medical resource use costs and overall survival had the greatest impact on ICER estimates. LIMITATIONS: This model is subject to uncertainty associated with extrapolating long-term treatment effects from shorter trial follow-up periods, although this would also be a limitation when using direct comparison or time-dependent hazard ratios. The NMA was limited by the use of indirect comparison, although sensitivity analyses supported the robustness of our findings. CONCLUSIONS: Our model demonstrated that dacomitinib is cost-effective for first-line EGFRm NSCLC treatment in Sweden vs afatinib and osimertinib.

Cost-Effectiveness of Sarilumab Added to Methotrexate in the Treatment of Adult Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors.

BACKGROUND: Despite a substantial number of treatment options in rheumatoid arthritis (RA) following tumor necrosis factor inhibitor (TNFi) inadequate response or intolerance (TNF-IR), a lack of clarity on the optimal approach remains. Sarilumab, a human monoclonal anti-interleukin-6 receptor alpha antibody, can be used as monotherapy or in combination with methotrexate or other conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) in TNF-IR patients. OBJECTIVE: To conduct a cost-utility analysis from a U.S. health care system perspective for sarilumab subcutaneous 200 mg + methotrexate versus abatacept + methotrexate or a bundle of TNFi + methotrexate for treatment of adult patients with moderately to severely active RA and TNF-IR. METHODS: Analysis was conducted via individual patient simulation based on patient profiles from the TARGET trial (NCT01709578); a 6-month decision tree was followed by lifetime semi-Markov model with 6-month cycles. Treatment response at 6 months, informed by network meta-analysis, was based on American College of Rheumatology (ACR) 20/50/70 criteria; patients achieving ≥ ACR20 continued with current therapy, and other patients moved to the next line of biologic DMARD therapy or conventional synthetic DMARD palliative treatment. Direct costs included wholesale acquisition drug costs and administration and routine care costs. Routine care costs and quality-adjusted life-years (QALYs) were estimated by predicting the Health Assessment Questionnaire Disability Index score based on treatment response and were imputed from published equations. RESULTS: Sarilumab + methotrexate dominated the TNFi bundle + methotrexate, achieving lower costs ($319,324 vs. $356,096) and greater effectiveness (4.27 vs. 4.15 QALYs), and was on the cost-efficiency frontier with abatacept + methotrexate ($360,211 and 4.29 QALYs). Abatacept + methotrexate was not cost-effective versus sarilumab + methotrexate. Scenario analyses indicated the results were robust; sarilumab + methotrexate became dominant against abatacept + methotrexate after reduced model horizon, minimum response based on ACR50 or ACR70, or time to discontinuation per treatment class. Sarilumab + methotrexate was also dominant versus the TNFi bundle; when class-specific time to treatment discontinuation was specified, sarilumab remained cost-effective with an incremental cost-effectiveness ratio of $36,894. CONCLUSIONS: Sarilumab + methotrexate can be considered an economically dominant (more effective, less costly) option versus a second TNFi + methotrexate; compared with abatacept + methotrexate, it is a less costly but less effective option for patients with moderately to severely active RA who have previously failed TNFi. DISCLOSURES: This study was funded by Sanofi and Regeneron Pharmaceuticals. Kiss and Gal are employees of Evidera, which received consulting fees from Sanofi/Regeneron for conducting this study. Muszbek was employed by Evidera at the time of this study. Kuznik and Chen are current employees of and stockholders in Regeneron Pharmaceuticals. Fournier is an employee of and stockholder in Sanofi. Proudfoot is a former employee of and current stockholder in Sanofi and current employee and stockholder in ViiV Healthcare/GlaxoSmithKline. Michaud has received grant funding from Pfizer and the Rheumatology Research Foundation. The sponsors were involved in the study design, collection, analysis, and interpretation of data as well as data checking of information provided in the manuscript. The authors had unrestricted access to study data, were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.

Economic Evaluation of Sarilumab in the Treatment of Adult Patients with Moderately-to-Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs.

INTRODUCTION: Assess the cost-effectiveness (US healthcare payer perspective) of sarilumab subcutaneous (SC) 200 mg + methotrexate versus conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) or targeted DMARD + methotrexate for moderate-to-severe rheumatoid arthritis (RA) in adults with inadequate response to methotrexate. METHODS: Microsimulation based on patient profiles from MOBILITY (NCT01061736) was conducted via a 6-month decision tree and lifetime Markov model with 6-monthly cycles. Treatment response at 6 months was informed by a network meta-analysis and based on American College of Rheumatology (ACR) response. Responders: patients with ACR20 response who continued with therapy; non-responders: ACR20 non-responders who transitioned to the subsequent treatment. Utilities and quality-adjusted life-years (QALYs) were estimated via mapping 6-month ACR20/50/70 response to relative change in Health Assessment Questionnaire Disability Index score (short term) and based on published algorithms (long term). Direct costs considered drugs (wholesale acquisition costs), administration and routine care. RESULTS: Lifetime QALYs and costs for treatment sequences on the efficiency frontier were 3.43 and $115,019 for active csDMARD, 5.79 and $430,918 for sarilumab, and 5.94 and $524,832 for etanercept (all others dominated). Sarilumab was cost-effective versus tocilizumab and csDMARD (incremental cost-effectiveness ratios of $84,079/QALY and $134,286/QALY). Probabilistic sensitivity analysis suggested comparable costs and slightly improved health benefits for sarilumab versus tocilizumab, irrespective of threshold. CONCLUSION: In patients with moderate-to-severe RA, sarilumab 200 mg SC every 2 weeks + methotrexate can be considered a cost-effective treatment option, with lower costs and greater health benefits than alternative treatment sequences (+ methotrexate) beginning with adalimumab, certolizumab, golimumab and tofacitinib and below commonly accepted cost-effectiveness thresholds against tocilizumab + methotrexate or csDMARD active treatment. FUNDING: Sanofi and Regeneron Pharmaceuticals, Inc.

Histological Assessment of a Combined Low-Level Laser/Light-Emitting Diode Therapy (685 nm/470 nm) for Sutured Skin Incisions in a Porcine Model: A Short Report.

OBJECTIVE: The aim of our study was to evaluate, from a histological point of view, the effect of photobiomodulation (PBM) with combined low-level laser therapy (LLLT)/light- emitting diode (LED) on porcine skin wound healing. BACKGROUND DATA: Most LLLT/LED wound healing studies have been performed on various types of rat models, with their inherent limitations. Minipigs are evolutionary and physiologically closer to humans than rats. MATERIALS AND METHODS: With the animals under general anesthesia, one full-thickness skin incision was performed on the back of each minipig (n = 10) and immediately closed using simple interrupted percutaneous sutures. The minipigs were randomly allocated into two groups: a PBM-treated group (LLLT λ = 685 nm, LED λ = 470 nm, both light sources producing power densities at 0.008 W/cm2; each light source delivering total daily doses of 3.36 J/cm2) and a sham-irradiated control group. Half of the animals in each group were killed on postoperative day 3, and the other half were killed on the postoperative day 7, and samples were removed for histological examination. RESULTS: Combined red and blue PBM accelerated the process of re-epithelization and formation of cross-linked collagen fibers compared with sham irradiated control wounds. CONCLUSIONS: Our results demonstrate that the current dose of combined red and blue PBM improves the healing of sutured skin incisions in minipigs.

Histological assessment of the effect of laser irradiation on skin wound healing in rats.

OBJECTIVE: The purpose of this study was to evaluate, from the histological point of view, the effect of diode laser irradiation on skin wound healing in Sprague-Dawley rats. BACKGROUND DATA: Various biological effects have been described in different studies after low-level laser therapy (LLLT). METHODS: Two parallel full-thickness skin incisions were performed on the back of each rat (n = 49) and immediately sutured. After surgery, one wound of each rat was exposed to laser irradiation (continuous mode, 670 nm, daily dose 30 J/cm2), whereas the parallel wound was not irradiated and served as control. Both wounds were removed 24, 48, 72, 96, 120, 144, and 168 h after surgery and routinely fixed and embedded in paraffin sections, stained with hematoxylin and eosin, van Gieson, periodic acid Schiff + periodic acid Schiff diastase, Mallory's phosphotungstic hematoxylin, and azur and eosin, and histopathologically evaluated. RESULTS: As compared to nonirradiated control wounds, laser stimulation shortened the inflammatory phase as well as accelerated the proliferative and maturation phase, and positively stimulated the regeneration of injured epidermis and the reparation of injured striated muscle. CONCLUSION: LLLT at 670 nm positively influences all phases of rat skin wound healing.