The role of quantitative bias analysis for nonrandomized comparisons in health technology assessment: recommendations from an expert workshop.

The use of treatment effects derived from nonrandomized studies (NRS) in health technology assessment (HTA) is growing. NRS carry an inherently greater risk of bias than randomized controlled trials (RCTs). Although bias can be mitigated to some extent through appropriate approaches to study design and analysis, concerns around data availability and quality and the absence of randomization mean residual biases typically render the interpretation of NRS challenging. Quantitative bias analysis (QBA) methods are a range of methods that use additional, typically external, data to understand the potential impact that unmeasured confounding and other biases including selection bias and time biases can have on the results (i.e., treatment effects) from an NRS. QBA has the potential to support HTA bodies in using NRS to support decision-making by quantifying the magnitude, direction, and uncertainty of biases. However, there are a number of key aspects of the use of QBA in HTA which have received limited discussion. This paper presents recommendations for the use of QBA in HTA developed using a multi-stakeholder workshop of experts in HTA with a focus on QBA for unmeasured confounding.

Cost-effectiveness of a new ACI technique for the treatment of articular cartilage defects of the knee compared to regularly used ACI technique and microfracture.

AIMS: For patients with cartilage defects of the knee, a new biocompatible and in situ cross-linkable albumin-hyaluronan-based hydrogel has been developed for matrix-associated autologous chondrocyte implantation (M-ACI) - NOVOCART Inject plus (Ninject; TETEC AG, Reutlingen, Germany). We aimed to estimate the potential cost-effectiveness of NInject, that is not available on the market, yet compared to spheroids of human autologous matrix-associated chondrocytes (Spherox; CO.DON GmbH, Leipzig, Germany) and microfracture. MATERIALS AND METHODS: An early Markov model was developed to estimate the cost-effectiveness in the United Kingdom (UK) from the payer perspective. Transition probabilities, response rates, utility values and costs were derived from literature. Since NInject has not yet been launched and no prices are available, its costs were assumed equal to those of Spherox. Cycle length was set at one year and the time horizon chosen was notional patients' remaining lifetime. Model robustness was evaluated with deterministic and probabilistic sensitivity analyses (DSA; PSA) and value of information analysis (VOIA). The Markov model was built using TreeAge Pro Healthcare. RESULTS: NInject was cost-effective compared to microfracture (ICER: £5,147) while Spherox was extendedly dominated. In sensitivity analyses, the ICER exceeded conventional WTP threshold of £20,000 only when the utility value after successful first treatment with NInject was decreased by 20% (ICER: £69,620). PSA corroborated the cost-effectiveness findings of NInject, compared to both alternatives, with probabilities of 60% of NInject undercutting the aforementioned WTP threshold and being the most cost-effective alternative. The VOIA revealed that obtaining additional evidence on the new technology will likely not be cost-effective for the UK National Health Service. LIMITATIONS AND CONCLUSION: This early Markov model showed that NInject is cost-effective for the treatment of articular cartilage defects in the knee, compared to Spherox and microfracture. However, as the final price of NInject has yet to be determined, the cost-effectiveness analysis performed in this study is provisional, assuming equal prices for NInject and Spherox.

Long-term cost-effectiveness of matrix-associated chondrocyte implantation in the German health care system: a discrete event simulation.

INTRODUCTION: Cartilage defects in the knee can be caused by injury, various types of arthritis, or degeneration. As a long-term consequence of cartilage defects, osteoarthritis can develop over time, often leading to the need for a total knee replacement (TKR). The treatment alternatives of chondral defects include, among others, microfracture, and matrix-associated autologous chondrocyte implantation (M-ACI). The purpose of this study was to determine cost-effectiveness of M-ACI in Germany with available mid- and long-term outcome data, with special focus on the avoidance of TKR. MATERIALS AND METHODS: We developed a discrete-event simulation (DES) that follows up individuals with cartilage defects of the knee over their lifetimes. The DES was conducted with a status-quo scenario in which M-ACI is available and a comparison scenario with no M-ACI available. The model included 10,000 patients with articular cartilage defects. We assumed Weibull distributions for short- and long-term effects for implant failures. Model outcomes were costs, number of TKRs, and quality-adjusted life years (QALYs). All analyses were performed from the perspective of the German statutory health insurance. RESULTS: The majority of patients was under 45 years old, with defect sizes between 2 and 7 cm2 (mean: 4.5 cm2); average modeled lifetime was 48 years. In the scenario without M-ACI, 26.4% of patients required a TKR over their lifetime. In the M-ACI scenario, this was the case in only 5.5% of cases. Thus, in the modeled cohort of 10,000 patients, 2700 TKRs, including revisions, could be avoided. Patients treated with M-ACI experienced improved quality of life (22.53 vs. 21.21 QALYs) at higher treatment-related costs (18,589 vs. 14,134 € /patient) compared to those treated without M-ACI, yielding an incremental cost-effectiveness ratio (ICER) of 3376 € /QALY. CONCLUSION: M-ACI is projected to be a highly cost-effective treatment for chondral defects of the knee in the German healthcare setting.

Multimorbidity in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results From a Longitudinal, Multicenter Data Linkage Study.

OBJECTIVE: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is considered a chronic, relapsing condition. To date, no studies have investigated multimorbidity in AAV nationally. This study was undertaken to characterize temporal trends in multimorbidity and report excess health care expenditures associated with multimorbidities in a national AAV cohort from Scotland. METHODS: Eligible patients with AAV were diagnosed between 1997 and 2017. Each patient was matched with up to 5 general population controls. Linked morbidity and health care expenditure data were retrieved from a Scottish national hospitalization repository and from published national cost data. Multimorbidity was defined as the development of ≥2 disorders. Prespecified morbidities, individually and together, were analyzed for risks and associations over time using modified Poisson regression, discrete interval analysis, and chi-square test for trend. The relationship between multimorbidities and health care expenditure was investigated using multivariate linear regression. RESULTS: In total, 543 patients with AAV (median age 58.7 years [range 48.9-68.0 years]; 53.6% male) and 2,672 general population controls (median age 58.7 years [range 48.9-68.0 years]; 53.7% male) were matched and followed up for a median of 5.1 years. AAV patients were more likely to develop individual morbidities at all time points, but especially <2 years after diagnosis. The highest proportional risk observed was for osteoporosis (adjusted incidence rate ratio 8.0, 95% confidence interval [95% CI] 4.5-14.2). After 1 year, 23.0% of AAV patients and 9.3% of controls had developed multimorbidity (P < 0.0001). After 10 years, 37.0% of AAV patients and 17.3% of controls were reported to have multimorbidity (P < 0.0001). Multimorbidity was associated with disproportionate increases in health care expenditures in AAV patients. Health care expenditure was highest for AAV patients with ≥3 morbidities (3.89-fold increase in costs, 95% CI 2.83-5.31; P < 0.001 versus no morbidities). CONCLUSION: These findings emphasize the importance of holistic care in patients with AAV, and may identify a potentially critical opportunity to consider early screening.

Potential Impact of IMbrave150 Results in the Evolving Treatment Landscape of Advanced Hepatocellular Carcinoma: A Multidisciplinary Expert Opinion.

A virtual expert roundtable was convened on April 16, 2020, to discuss the evolving landscape of care for treating patients with advanced hepatocellular carcinoma (HCC) and discuss questions related to patient care and treatment selection. This commentary presents highlights from this discussion and provides an expert opinion about approaches to treatment for HCC in the Americas and the European Union. We anticipate that atezolizumab plus bevacizumab will become the standard of care for advanced HCC patients. However, this approach will make decisions regarding the sequencing of treatments for second-line therapies and beyond more challenging. Therapy will require individualization based on patient characteristics and preferences, while insurance coverage decisions and requirements may also impact the options that patients can access. Additional research regarding prognostic and predictive biomarkers is needed to help better identify optimal treatment approaches for specific patient populations. Multidisciplinary tumor boards will continue to play a critical role in guiding treatment selection for individual patients. Atezolizumab plus bevacizumab offers a promising new first-line therapeutic option for patients with advanced HCC, but more research is needed to optimize and individualize patient therapy.

Transitioning to community-based mental health service delivery: opportunities for Ukraine.

Background and objectives: Ukraine's mental health system has been found to be inadequate and unresponsive to the needs of the population, in view of its emphasis on inpatient service delivery. This study sought to identify potential changes to the organization and financing of mental health services within the Ukrainian health system that would facilitate the delivery of mental health services in a community-based setting. Methodology: A systematic literature review was undertaken to identify organizational and financing features that have been successfully used to enable and incentivize the delivery of community-based mental health services in Central or Eastern European and/or former Soviet Union countries. Results: There was limited literature on the organizational and financing features that facilitate the delivery of community-based care. Key facilitators for transitioning from institution-based to community-based mental health service delivery include; a clear vision for community-based care, investment in the mental health system, and mechanisms that allow health funding to follow the patient through the health system. Conclusions: Ukraine should adopt strategic purchasing mechanisms to address inefficiency in the financing of its mental health system, and prioritize collaborative planning and delivery of mental health services. Ongoing reform of the Ukrainian health system provides momentum for instituting such changes.

Budget Impact Analysis of a Home-Based Nutrition Program for Adults at Risk for Malnutrition.

BACKGROUND: Hospital-based, nutrition-focused interventions have significantly lowered the cost-associated burden of poor nutrition through a reduction in healthcare resource utilization (HCRU). However, for patients at risk for poor nutrition who receive nutritional care at home, limited evidence exists on the economic impact of nutrition-focused interventions. OBJECTIVE: To estimate the 30-day cost-savings associated with an at-home nutrition-focused quality improvement program in the postacute care setting for patients at risk for poor nutrition from the perspective of a hospital system. METHODS: We compared the HCRU of 1546 patients enrolled in a quality improvement program during 1 year versus 7413 patients in a pre-program historical cohort who received care during the 1 year before the quality improvement program implementation. The analysis included the number of 30-day hospitalizations, emergency department and outpatient visits for both cohorts, and the associated costs. The main analysis included the fixed and variable costs for the program, and the costs of oral nutritional supplement and delivery. The costs for hospitalization, emergency department, and outpatient visit costs were based on the 2013 Healthcare Cost and Utilization Project and Medical Expenditure Panel Survey. RESULTS: Based on the 2013 survey, the baseline costs for hospitalization, emergency department, and outpatient visit costs were $18,296, $1312, and $535, respectively. Our health economic analysis about the 30-day overall HCRU has shown that the quality improvement program group resulted in a total cost-savings of $2,408,668 for the 1546 patients in the program and a net savings of $1558 per patient compared with the costs for the pre-quality improvement program historical cohort. CONCLUSION: The use of a nutrition-focused quality improvement program led to significant 30-day cost-savings, by reducing HCRU for adults who received nutritional-based care at home. The improvements in HCRU highlight the importance of implementing nutrition-focused quality improvement programs for hospital systems that provide care for patients who are at risk for poor nutrition across a variety of care settings.

Effect of age on the effectiveness of the first-line standard of care treatment in patients with metastatic colorectal cancer: systematic review of observational studies.

PURPOSE: Most metastatic colorectal cancer (mCRC) patients are elderly. This systematic review identifies and describes observational studies evaluating the influence of age on first-line treatment effectiveness in real-world practice. METHODS: Medline and EMBASE were searched up to May 2016. The included studies were those that investigated first-line treatment of mCRC and reported age groups and overall survival (OS), progression-free survival (PFS) or overall response rate (ORR) were included. Studies published before 2008 were excluded. Study quality was assessed using the Newcastle-Ottawa Scale. Data were evaluated by age group (< 70 vs. ≥ 70 years; 65-75 vs. ≥ 75 years) and outcome. A pooled survival median was calculated for patients (cutoff = 70 years). RESULTS: In total, 11 articles with 11,063 patients were included. Four studies using a cutoff of 70 years of age reported OS and PFS, and two studies reported ORRs. In terms of OS, all studies showed a higher OS for those < 70 years of age than for those ≥ 70 years of age. PFS did not find differences by age. For ORRs, one study favoured the younger group, while the second study did not differ by age. Based on three studies, the pooled medians for < 70 years of age and ≥ 70 years of age were the same for PFS (10.2) and were 27.0 and 22.9 for OS, respectively. All included studies were of high or acceptable quality. CONCLUSIONS: The results suggest that age has no effect on PFS. For ORR, the results were inconsistent between studies. Younger patients in general had better OS, which might be partly explained by more aggressive treatment. This treatment seemed not to be guided by performance status or number of metastatic sites.

Event and Cost Offsets of Switching 20% of the Type 1 Diabetes Population in Germany From Multiple Daily Injections to Continuous Subcutaneous Insulin Infusion: A 4-Year Simulation Model.

BACKGROUND: Most patients with type 1 diabetes (T1D) administer insulin by multiple daily injections (MDI). However, continuous subcutaneous insulin infusion (CSII) therapy has been shown to improve glycemic control compared with MDI. OBJECTIVE: The objective was to determine the key medical event and cost offsets generated over a 4-year period by introducing CSII to T1D patients who have inadequately controlled glucose metabolism on MDI in Germany. METHODS: A decision-analytic budget impact model, simulating a treatment switch scenario, was developed. In the base case, all T1D patients received MDI, while in the switch scenario, 20% of the eligible T1D population, randomly selected, moved to CSII. The model focused on 2 medical endpoints and their corresponding cost offsets: severe hypoglycemic events requiring hospitalization (SHEH) and complication-borne diabetic events (CDEs) avoided. Event rates and costs were taken from the literature and official sources, adopting a health insurance perspective. RESULTS: Compared with the base case, treating 20% of patients with CSII in the switch scenario resulted in 47 864 fewer SHEH and 5543 fewer CDEs. This led to total cost offsets of €183 085 281 within the 4-year time horizon. Of these, 92% were driven by avoided SHEH. Compared to an expected budget impact (cost increase) of 83%, only treatment costs considered, the total impact of the switch scenario amounted merely to a 24.5% increase in costs (reduction by 58.5% points; a factor of 3.4). CONCLUSION: The use of CSII resulted in fewer SHEH and CDEs compared to MDI. The incurred CSII implementation costs are hence offset to a substantial degree by cost savings in complication treatment.

The value of childhood combination vaccines: From beliefs to evidence.

Although vaccination is one of the most cost-effective health care interventions, under-vaccination and variation in coverage rates lower than policy targets is rising in developed countries, partly due to concerns about vaccination value and benefits. By merging various antigens into a single product, combination vaccines represent a valuable tool to mitigate the burden associated with the numerous injections needed to protect against vaccine preventable infectious diseases and increase coverage rate, possibly through various behavioral mechanisms which have yet to be fully explored. Beyond their cost-effectiveness in protecting against more diseases with fewer injections, combination vaccines also have several other benefits, for children, their parents/carers, as well as for the health system and the population as a whole. The objectives of this review are to identify and illustrate the value of combination vaccines for childhood immunization. Evidence was classified into 2 groups: benefits for society and benefits for public health and healthcare systems. This article also highlights the value of innovation and challenges of combination vaccine development as well as the need for an increased number of suppliers to mitigate the impact of any potential vaccine shortage. Increasing public confidence in vaccines and combination vaccines is also critical to fully exploit their benefits.

Vaccination: the cornerstone of an efficient healthcare system.

Vaccination has made an important contribution to the decreased incidence of numerous infectious diseases and associated mortality. In 2013, it was estimated that 103 million cases of childhood diseases in the United States had been prevented by the use of vaccines since 1924. These health effects translate into positive economic results, as vaccination can provide significant savings by avoiding the direct and indirect costs associated with treating the disease and possible long-term disability. A recent US study estimated that every dollar spent on childhood vaccination could save US$3 from a payer perspective and US$10 from a societal perspective. The first vaccines set a high standard from a public health 'return on investment' perspective, because they are highly cost-saving. Today, however, where only a few healthcare interventions are considered to be cost-saving, the challenge that decision-makers typically face is to identify such healthcare interventions that are deemed cost-effective, that is, provide extra benefit at a reasonable extra cost. Some of the newer vaccines provide a solution to some of today's important health issues, such as cervical cancers with human papillomavirus vaccines, or debilitating diseases with herpes zoster vaccines. These recent, more expensive vaccines have been shown to be cost-effective in several economic analyses. Overall, vaccination can still be regarded as one of the most cost-effective healthcare interventions.

Quality of life in Parkinson's disease patients with motor fluctuations and dyskinesias in five European countries.

BACKGROUND: Little is known about the relationship between specific subtypes of treatment-associated motor complications and different domains of health-related Quality of Life (QoL) in patients with Parkinson's disease (PD). Larger studies that investigate these aspects within a cross-cultural setting are scarce. OBJECTIVE: To assess QoL and its association with on-off fluctuations, peak-dose dyskinesias, biphasic dyskinesias, and off-dystonias in PD patients from five European countries. METHODS: Data from 817 PD patients were collected cross-sectionally in France, Germany, Italy, Spain, and the UK. QoL was measured with the generic EuroQoL 5-Dimension questionnaire (EQ-5D) and the disease-specific Parkinson's Disease Questionnaire-39 (PDQ-39). Multivariable linear regression analyses were performed to test the associations of motor complication subtypes with QoL. RESULTS: Thirty-three percent of the patients (varying from 23% in Italy to 58% in France) suffered from motor complications, either a single subtype or a combination of different subtypes. On-off fluctuations were associated with a 7.1 percentage point decrease in the EQ-5D (p < 0.001) and a 3.6 percentage point deterioration in the PDQ-39 (p = 0.01). Dyskinesias were not seen to affect global QoL scores, but had detrimental effects on the PDQ-39 dimensions activities of daily living, cognitions, stigma, and bodily discomfort. Patients from Spain, Italy, and France had lower global QoL scores in the multivariable analyses than patients from Germany and the UK. CONCLUSION: Motor complications, primarily on-off fluctuations, may impact QoL in PD patients. This substantiates the importance of clinical strategies targeting the prevention, delay of onset, and management of motor complications in PD patients.

Pancreatic enzyme replacement therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis: a 1-year disease management study on symptom control and quality of life.

OBJECTIVE: Exocrine pancreatic insufficiency (EPI) is frequent in patients with chronic pancreatitis (CP). This 1-year, prospective, multicenter, observational, disease management study aimed to assess symptom improvement and quality of life in patients with CP with EPI who were receiving pancreatic enzyme replacement. METHODS: Patients with CP and chronic EPI were either assigned to cohort 1 that consisted of patients already taking pancreatin (Kreon; Abbott Arzneimittel GmbH, Hannover, Germany) or cohort 2 that consisted of patients with newly diagnosed EPI without prior pancreatic enzyme treatment. Symptoms were documented, and quality of life was assessed using the gastrointestinal quality of life index (GIQLI) at baseline, 6 months, and 1 year. RESULTS: A total of 294 patients were evaluated (cohort 1, n = 206; cohort 2, n = 88). The proportion of patients experiencing gastrointestinal symptoms and recurrent pain after 1 year was significantly reduced in both cohorts (P < 0.001). The alleviation of symptoms was reflected in GIQLI score improvements at 1 year in both cohorts (P < 0.001), independent of CP severity and etiology. Improvements in GIQLI score were more pronounced in cohort 2 (P < 0.001). CONCLUSIONS: Pancreatin demonstrated symptom relief and improvement in quality of life in patients with CP-related EPI in this disease management study.

Do neurologists in Germany adhere to the national Parkinson's disease guideline?

Implementation of guidelines can improve clinical practice. The aim in this study was to investigate whether neurologists in Germany adhered to the national Parkinson's disease guideline. Data were obtained from a cross-sectional survey of 60 neurologists. Analyses were performed on 320 patients with idiopathic Parkinson's disease with either low grades of functional impairment (Hoehn and Yahr stage I) or higher grades of functional impairment (stage II-V) but without motor complications. The sample was divided into four groups depending on age and grade of functional impairment. For each group, a biometric parameter on the use of dopamine agonists and L-dopa was defined based on the guideline. In patients aged <70 years, the recommendation to use dopamine agonists without L-dopa (parameter 1) was observed in 53% of patients with lower grades of functional impairment, whilst recommended use of dopamine agonists in more functionally impaired patients (parameter 2) was followed to a greater extent (84%). In patients aged ≥70 years, recommendations to use L-dopa without dopamine agonists were adhered to in only 50% of less functionally impaired (parameter 3) and 52% of more functionally impaired (parameter 4) patients. In conclusion, our results indicated there was moderate but not full adherence to the guideline.

Cost-utility analysis of eprosartan compared to enalapril in primary prevention and nitrendipine in secondary prevention in Europe--the HEALTH model.

OBJECTIVE: To investigate the cost-utility of eprosartan versus enalapril (primary prevention) and versus nitrendipine (secondary prevention) on the basis of head-to-head evidence from randomized controlled trials. METHODS: The HEALTH model (Health Economic Assessment of Life with Teveten for Hypertension) is an object-oriented probabilistic Monte Carlo simulation model. It combines a Framingham-based risk calculation with a systolic blood pressure approach to estimate the relative risk reduction of cardiovascular and cerebrovascular events based on recent meta-analyses. In secondary prevention, an additional risk reduction is modeled for eprosartan according to the results of the MOSES study ("Morbidity and Mortality after Stroke--Eprosartan Compared to Nitrendipine for Secondary Prevention"). Costs and utilities were derived from published estimates considering European country-specific health-care payer perspectives. RESULTS: Comparing eprosartan to enalapril in a primary prevention setting the mean costs per quality adjusted life year (QALY) gained were highest in Germany (Euro 24,036) followed by Belgium (Euro 17,863), the UK (Euro 16,364), Norway (Euro 13,834), Sweden (Euro 11,691) and Spain (Euro 7918). In a secondary prevention setting (eprosartan vs. nitrendipine) the highest costs per QALY gained have been observed in Germany (Euro 9136) followed by the UK (Euro 6008), Norway (Euro 1695), Sweden (Euro 907), Spain (Euro -2054) and Belgium (Euro -5767). CONCLUSIONS: Considering a Euro 30,000 willingness-to-pay threshold per QALY gained, eprosartan is cost-effective as compared to enalapril in primary prevention (patients >or=50 years old and a systolic blood pressure >or=160 mm Hg) and cost-effective as compared to nitrendipine in secondary prevention (all investigated patients).

Drug related problems with Antiparkinsonian agents: consumer Internet reports versus published data.

PURPOSE: There is currently a lack of detailed information concerning drug related problems in the outpatient treatment of Parkinson's disease. METHODS: Problems associated with drug treatment communicated anonymously in Parkinson's disease online forums were therefore retrospectively searched and documented for 1 year. RESULTS: Based on postings concerning 12 drugs for the treatment of Parkinson's disease, a total of 238 drug related problems were identified and categorised using the Problem Intervention Documentation (PI-Doc). Of these, 153 were adverse drug reactions. Adverse drug reactions associated with the skin were relatively common, but central effects such as cognitive or psychiatric changes, effects on the sleep/waking system and other problems like headache and dizziness accounted for the highest percentage of adverse events. A comparison with data from scientific literature revealed a number of differences. This means that an analysis of online forums detected a number of drug related problems that were otherwise largely invisible. These were mainly associated with the qualitative aspects of treatment such as medication handling, dosage and individual problems concerning adverse events. In addition, the described method of identifying and classifying drug related problems in Internet forums may also be seen as a contribution to the international discussion about consumer reports and pharmacovigilance. The information about adverse drug reactions given by Internet users can be seen as a valuable adjunct to clinical trial data and as being very timely with regard to the event itself. CONCLUSION: Online forums may be considered as a suitable source of observational information to complement data from randomised clinical trials.