FOUNTAIN: a modular research platform for integrated real-world evidence generation.

BACKGROUND: Real-world evidence (RWE) plays a key role in regulatory and healthcare decision-making, but the potentially fragmentated nature of generated evidence may limit its utility for clinical decision-making. Heterogeneity and a lack of reproducibility in RWE resulting from inconsistent application of methodologies across data sources should be minimized through harmonization. METHODS: This paper's aim is to describe and reflect upon a multidisciplinary research platform (FOUNTAIN; FinerenOne mUlti-database NeTwork for evidence generAtIoN) with coordinated studies using diverse RWE generation approaches and explore the platform's strengths and limitations. With guidance from an executive advisory committee of multidisciplinary experts and patient representatives, the goal of the FOUNTAIN platform is to harmonize RWE generation across a portfolio of research projects, including research partner collaborations and a common data model (CDM)-based program. FOUNTAIN's overarching objectives as a research platform are to establish long-term collaborations among pharmacoepidemiology research partners and experts and to integrate diverse approaches for RWE generation, including global protocol execution by research partners in local data sources and common protocol execution in multiple data sources through federated data networks, while ensuring harmonization of medical definitions, methodology, and reproducible artifacts across all studies. Specifically, the aim of the multiple studies run within the frame of FOUNTAIN is to provide insight into the real-world utilization, effectiveness, and safety of finerenone across its life-cycle. RESULTS: Currently, the FOUNTAIN platform includes 9 research partner collaborations and 8 CDM-mapped data sources from 7 countries (United States, United Kingdom, China, Japan, The Netherlands, Spain, and Denmark). These databases and research partners were selected after a feasibility fit-for-purpose evaluation. Six multicountry, multidatabase, cohort studies are ongoing to describe patient populations, current standard of care, comorbidity profiles, healthcare resource use, and treatment effectiveness and safety in different patient populations with chronic kidney disease and type 2 diabetes. Strengths and potential limitations of FOUNTAIN are described in the context of valid RWE generation. CONCLUSION: The establishment of the FOUNTAIN platform has allowed harmonized execution of multiple studies, promoting consistency both within individual studies that employ multiple data sources and across all studies run within the platform's framework. FOUNTAIN presents a proposal to efficiently improve the consistency and generalizability of RWE on finerenone.

How can we optimise health technology assessment and reimbursement decisions to accelerate access to new cardiovascular medicines?

Regulatory approvals of, and subsequent access to, innovative cardiovascular medications have declined. How much of this decline relates to the final step of gaining reimbursement for new treatments is unknown. Payers and health technology assessment (HTA) bodies look beyond efficacy and safety to assess whether a new drug improves patient outcomes, quality of life, or satisfaction at a cost that is affordable compared to existing treatments. HTA bodies work within a limited healthcare budget, and this is one of the reasons why only half of newly approved drugs are accepted for reimbursement, or receive restricted or "optimised" recommendations from HTA bodies. All stakeholders have the common goal of facilitating access to safe, effective, and affordable treatments to appropriate patients. An important strategy to expedite this is providing optimal data. This is demonstrably facilitated by early (and ongoing) discussions between all stakeholders. Many countries have formal programmes to provide collaborative regulatory and HTA advice to developers. Other strategies include aligning regulatory and HTA processes, increasing use of real-world evidence, formally defining the decision-making process, and educating stakeholders on the criteria for positive decision making. Industry should focus on developing treatments for unmet medical needs, seek early engagement with HTA and regulatory bodies, improve methodologies for optimal price setting, develop internal systems to collaborate with national and international stakeholders, and conduct post-approval studies. Patient involvement in all stages of development, including HTA, is critical to capture the lived experience and priorities of those whose lives will be impacted by new treatment approvals.

Series: Pragmatic trials and real world evidence: Paper 8. Data collection and management.

Pragmatic trials can improve our understanding of how treatments will perform in routine practice. In a series of eight papers, the GetReal Consortium has evaluated the challenges in designing and conducting pragmatic trials and their specific methodological, operational, regulatory, and ethical implications. The present final paper of the series discusses the operational and methodological challenges of data collection in pragmatic trials. A more pragmatic data collection needs to balance the delivery of highly accurate and complete data with minimizing the level of interference that data entry and verification induce with clinical practice. Furthermore, it should allow for the involvement of a representative sample of practices, physicians, and patients who prescribe/receive treatment in routine care. This paper discusses challenges that are related to the different methods of data collection and presents potential solutions where possible. No one-size-fits-all recommendation can be given for the collection of data in pragmatic trials, although in general the application of existing routinely used data-collection systems and processes seems to best suit the pragmatic approach. However, data access and privacy, the time points of data collection, the level of detail in the data, and the lack of a clear understanding of the data-collection process were identified as main challenges for the usage of routinely collected data in pragmatic trials. A first step should be to determine to what extent existing health care databases provide the necessary study data and can accommodate data collection and management. When more elaborate or detailed data collection or more structured follow-up is required, data collection in a pragmatic trial will have to be tailor-made, often using a hybrid approach using a dedicated electronic case report form (eCRF). In this case, the eCRF should be kept as simple as possible to reduce the burden for practitioners and minimize influence on routine clinical practice.

A multi-country economic evaluation of low-dose aspirin in the primary prevention of cardiovascular disease.

BACKGROUND: Low-dose aspirin (acetylsalicylic acid) is standard care in patients with a history of cardiovascular disease (CVD). The use of low-dose aspirin in primary prevention is not yet fully established, although meta-analyses and US and European guidelines support its use in people at increased risk of CVD. The primary objective of this study was to assess the economic consequences of the use of low-dose aspirin in the primary prevention of CVD in four European countries (UK, Germany, Spain and Italy). METHODS: Based on results (benefits and harms) reported in meta-analyses, a state-transition model was developed to predict the cost effectiveness of low-dose aspirin in the primary prevention of CVD. The model consists of five health states: no history of CVD, history of stroke, history of myocardial infarction (MI), history of stroke and MI, and death. A 10-year time horizon and 1-year cycles were used. Secondary prevention data were derived from the aspirin arm of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) study. Direct costs from the public healthcare payer's perspective were used (euro, 2003 values). Effects were expressed in life-years (LY) and QALYs gained. Quality weights were obtained from published data.Country-specific discounting was applied on effects and costs (3.5% for the UK, 5% for Germany and 3% for Spain and Italy). Univariate sensitivity analysis and Monte Carlo simulation were performed to assess uncertainty in the results. RESULTS: For patients with an annual risk of coronary heart disease (CHD) of 1.5%, the model resulted in 10-year savings with low-dose aspirin of on average euro 201 (95% CI 81, 331), euro 281 (95% CI 141, 422), euro 797 (95% CI 301, 1331) and euro 427 (95% CI 122, 731) per patient in the UK, Germany, Spain and Italy, respectively. Average total cost was almost 3- to 4-fold higher in Spain and Italy than in the UK and Germany. Savings (non-significant) start in the first year of treatment in all countries. Sensitivity analyses on cost of complications, utility, discounting, stroke rate and gastrointestinal bleeding rate showed the robustness of the results. From an annual risk of CHD of 0.236% for the UK, 0.324% for Germany, 0.244% for Spain and 0.560% for Italy, low-dose aspirin was cost saving compared with placebo. Monte Carlo analysis showed aspirin dominance in about 97% of cases for the three studied annual risks of CHD (0.6%, 1.0% and 1.5%) in the UK, Germany and Spain. In Italy, aspirin dominance in > 95% of cases was seen at annual risks of 1% and 1.5%. CONCLUSIONS: Administering low-dose aspirin to patients with an annual risk of CHD of > or = 1% appears to be significantly cost saving from the healthcare payer's perspective in all countries analysed. Sensitivity analyses (CHD risk and bleedings) suggested the results were robust.

A comparative review of health-related quality-of-life measures for use in HIV/AIDS clinical trials.

With the advent of highly active antiretroviral therapy (HAART), HIV-infected patients are living longer and are concerned not only with a treatment's ability to extend their life but also with the quality of the life they are able to lead. Regulatory authorities are also paying closer attention to the use of health-related quality-of-life (HR-QOL) measures in clinical trials and to the subsequent claims that are made based on the results. This paper reviews existing HR-QOL measures reported in the HIV/AIDS literature since 1990 and identifies those most worthy of consideration for use in future clinical trials.A comprehensive review following predefined selection criteria was conducted. Generic and HIV-targeted measures were assessed for content and practicality for the clinical trial setting. The generic measures were additionally reviewed for the ability to produce preference-based index scores and for the existence of normative general population data. Three generic and six HIV-targeted measures met these selection criteria and were then assessed more fully in terms of their development (HIV-targeted measures), psychometric properties and appropriateness for use in clinical trials.It was determined that each of the selected generic measures (i.e. Medical Outcomes Study [MOS] 36-Item Short Form Survey Instrument [SF-36], EQ-5D, Health Utilities Index [HUI]) could serve as a useful adjunct to an HIV-targeted measure in a trial. The Functional Assessment of HIV Infection (FAHI) and MOS-HIV health survey were deemed the two most appropriate HIV-targeted measures. Each of the measures can be self-administered in < or = 10 minutes and there was ample evidence of their excellent psychometric properties. However, they would not be optimal in all HIV-infected subgroups (e.g. treatment naive vs advanced; adolescents vs older adults) targeted for clinical trial interventions. Although there is no one best HR-QOL measure for use in HIV/AIDS clinical trials, based on our review criteria we identified three generic and two HIV-targeted candidate measures. However, these measures have their limitations and it is clear that greater consensus needs to develop regarding more effective and efficient approaches to HR-QOL measurement in HIV/AIDS clinical trials. Along with the increasingly complex HR-QOL measurement task resulting from changes in the HIV-infected population and shifts in the HR-QOL burden associated with HIV infection and its treatment over the past 25 years, it is increasingly important that HR-QOL outcomes become viable endpoints in HIV/AIDS clinical trials.

[Health economic evaluation of low-dose acetylsalicylic acid in the primary prevention of cardiovascular disease]. / Evaluación económica del tratamiento con ácido acetilsalicílico en dosis bajas en la prevención primaria de enfermedades cardiovasculares.

INTRODUCTION AND OBJECTIVES: Low-dose aspirin is standard treatment for patients with a history of cardiovascular disease. Its use in primary prevention is more controversial. However, recent studies also support the use of aspirin in high-risk individuals with no history of cardiovascular disease. This study investigated the health economic implications of using low-dose aspirin in the primary prevention of cardiovascular disease in Spain. METHODS: A model was developed to predict the cost-effectiveness of low-dose aspirin in the primary prevention of cardiovascular disease over a period of 10 years. The direct costs used were those of the Spanish National Health Service (NHS). Results were expressed as cost per life-year gained and per quality-adjusted life-year gained. RESULTS: Administering low-dose aspirin to an individual with a 10-year risk of coronary heart disease > or =15% resulted in an average net saving of e 797 (95% CI, e 263-1331) over the 10-year period, with savings starting in the first year. For an annual risk > or =0.24%, this form of treatment would reduce NHS costs. Treating all at-risk individuals in the Spanish population with aspirin would save e 26.5 million from the healthcare budget, starting in the first year. CONCLUSIONS: Administering low-dose aspirin to individuals with a 10-year risk of coronary heart disease > or =15% would result in significant cost savings for the Spanish NHS. Sensitivity analysis confirmed the robustness of these findings.

Disease burden and unmet needs for prevention of venous thromboembolism in medically ill patients in Europe show underutilisation of preventive therapies.

It was the aim of this review to assess the incidence of venous thromboembolism (VTE) and current practice patterns for VTE prophylaxis among medical patients with acute illness in Europe. A literature search was conducted on the epidemiology and prophylaxis practices of VTE prevention among adult patients treated in-hospital for major medical conditions. A total of 21 studies with European information published between 1999 and April 2010 were retrieved. Among patients hospitalised for an acute medical illness, the incidence of VTE varied between 3.65% (symptomatic only over 10.9 days) and 14.9% (asymptomatic and symptomatic over 14 days). While clinical guidelines recommend pharmacologic VTE prophylaxis for patients admitted to hospital with an acute medical illness who are bedridden, clear identification of specific risk groups who would benefit from VTE prophylaxis is lacking. In the majority of studies retrieved, prophylaxis was under-used among medical inpatients; 21% to 62% of all patients admitted to the hospital for acute medical illnesses did not receive VTE prophylaxis. Furthermore, among patients who did receive prophylaxis, a considerable proportion received medication that was not in accord with guidelines due to short duration, suboptimal dose, or inappropriate type of prophylaxis. In most cases, the duration of VTE prophylaxis did not exceed hospital stay, the mean duration of which varied between 5 and 11 days. In conclusion, despite demonstrated efficacy and established guidelines supporting VTE prophylaxis, utilisation rates and treatment duration remain suboptimal, leaving medical patients at continued risk for VTE. Improved guideline adherence and effective care delivery among the medically ill are stressed.

Cost-effectiveness of empirical prescribing of antimicrobials in community-acquired pneumonia in three countries in the presence of resistance.

OBJECTIVES: To assess the cost-effectiveness of empirical outpatient treatment options for community-acquired pneumonia (CAP) in France, the USA and Germany, representing high, moderate and low antimicrobial resistance prevalence, respectively. METHODS: A decision analytic model was developed for mild-to-moderate CAP outpatient treatment. Treatment algorithms incorporated follow-up after treatment failure due to resistance or other reasons. First-line treatment included moxifloxacin, beta-lactams, macrolides or doxycycline; second-line treatment used a different antimicrobial class. Country-specific resistance and co-resistance prevalences to first- and second-line therapy for the major CAP pathogens were derived from surveillance studies. Clinical failure rates due to antimicrobial-susceptible and -resistant pathogens were obtained from the literature or estimated. Total costs were estimated using standard sources and a third-party payer perspective. Outcome measures included first-line clinical failures avoided, second-line treatments avoided and hospitalizations avoided. Incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: First-line moxifloxacin treatment followed by co-amoxiclav dominated all other treatments in France, the USA and in Germany for all outcome measures. Sensitivity analyses maintained moxifloxacin dominance in France and the USA but affected ICERs in some cases in Germany. CONCLUSIONS: Antimicrobial resistance/spectrum have a significant impact on outcomes and costs in empirical outpatient CAP treatment. Despite low acquisition costs for generic antibiotics, first-line treatment effective against the major CAP pathogens, including strains resistant to other antimicrobials, resulted in better clinical outcomes in all countries and lower treatment costs for all.

A health economic evaluation of aspirin in the primary prevention of cardiovascular disease in Japan.

OBJECTIVE: Low-dose aspirin is standard care in patients with a history of cardiovascular disease (CVD). But, the use of low-dose aspirin in primary prevention has not yet been fully established in Japan although meta-analyses and US/European guidelines support its use in persons at increased CVD risk. This study assessed the health economic consequences of the use of low-dose aspirin in the primary prevention of CVD in Japan. PATIENTS AND METHODS: Based on results reported in two recent meta-analyses of Hayden (2002) and Eidelman (2003), a Markov model was constructed to predict the cost-effectiveness of low-dose aspirin in the primary prevention of CVD. The model consists of 5 health states: 1) no history of CVD, 2) history of stroke, 3) history of myocardial infarction, 4) history of CVD, and 5) death, with a 10-year time horizon and 1-year cycles. Direct costs from the insurers' perspective were used, while health outcome was expressed in Life-Years Gained (LYG). 'Discounting Rate' with 3% was applied on effectiveness and costs. RESULTS: For patients with a 1-year risk of coronary heart disease (CHD) of 1.5% (10-year risk of +/-15%), the model demonstrated 'dominance' of the 'aspirin' arm versus 'no aspirin' arm; the 10-year costs were Japanese Yen (JPY) 634,000 (Euro 4,857) and JPY 518,000 (Euro 3,968) in the 'no aspirin' arm and 'aspirin' arm, respectively, while LYG was 8.33 and 8.36, respectively. Low-dose aspirin treatment saved on average JPY 116,000 (Euro 889) [95% confidence interval (CI) JPY 57,077-175,151] per patient. Dominance was demonstrated (non-significant) in the first year of treatment and, low-dose aspirin was dominant to 'no aspirin' arm from an annual risk of 0.20%. Other results of sensitivity analysis on gastrointestinal (GI) bleeding rate, stroke rate, cost of each event and discounting showed the robustness of the results. CONCLUSIONS: Administering low-dose aspirin to patients with a 1-year risk of CHD of 1.5% and more is significantly cost-saving from the insurers' perspective in Japan.

Development and validation of a risk score for somatic erectile dysfunction: combined results from three cross-sectional surveys.

OBJECTIVES: Some men with erectile dysfunction (ED) have difficulties discussing their condition with their physicians. Existing screening and diagnostic tools for ED often require the administration of personal questions regarding the condition. We present a simple risk score to estimate the individual likelihood of somatic ED, based on age and existing health conditions. METHODS: Data from the Cologne Male Survey (n = 4396) were used to develop a multivariable logistic regression model for the individual ED likelihood. The regression equation was both internally and externally validated using data from a national study (Berlin study) and a multinational cross-sectional study (MALES study). RESULTS: A final regression equation including age, pelvic surgery, diabetes mellitus, arterial circulatory disorder, heart disease, smoking, and hypertension reached an area under the receiver operating characteristic curve of 0.84 (0.5 means random and 1.0 perfect discrimination). Internal validation did not indicate any relevant overfit and the external validation results (national data: AUC = 0.75; multinational data: AUC = 0.67) are similar to those of other popular risk scores. CONCLUSIONS: The validated ED risk score developed from the regression equation can be used as a screening tool to identify patients who are at a high risk of somatic ED. This tool can facilitate entering into discussions between physicians and patients regarding erectile function.

The treatment satisfaction scale: a multidimensional instrument for the assessment of treatment satisfaction for erectile dysfunction patients and their partners.

BACKGROUND: The development of the Treatment Satisfaction Scale (TSS) was previously reported (Kubin et al., 2004). OBJECTIVE: This article describes the psychometric validation process and psychometric properties (e.g., reliability, validity, and responsiveness) of TSS. METHODS: Initial patient and partner questionnaires were administered in a multi-national clinical trial. On the basis of exploratory analyses, iterative psychometric testing, and consideration of face validity and interpretability, the number of items was reduced, and six scales were constructed: "Satisfaction with Medication," "Ease with Erection," "Satisfaction with Erectile Function," "Pleasure from Sexual Activity," "Satisfaction with Orgasm," and either "Sexual Confidence" (for patients) or "Confidence in Completion" (for partners). RESULTS: Multi-item scales had good internal consistency reliability and concurrent validity with the IIEF. All patient scales and most partner scales were valid in relation to clinical criteria, and all tested scales were responsive to change over time. CONCLUSION: The TSS is brief, culturally valid, and the most comprehensive multidimensional measure of satisfaction with ED treatment for patients and their partners, and addresses some of the shortcomings of existing measures.

Modeling costs and cost-effectiveness of different CMV management strategies in liver transplant recipients as a support for current and future decision making.

OBJECTIVES: To develop a generic decision-analytic model to predict health and economic outcomes of different management options for cytomegalovirus (CMV) infection and disease in liver transplant patients. METHODS AND DATA: The model considers different CMV management strategies, thereby emphasizing the important difference between infection and disease. The first strategy starts with prophylaxis prior to transplantation, followed by preemptive treatment if infection, based on positive CMV diagnostic tests, is confirmed. The second strategy is a preemptive strategy consisting of only testing followed by preemptive treatment. Finally, in the wait-and-treat strategy, antiviral treatment is only started when clinical signs of CMV disease appear. Management and resource-use data were obtained from clinical experts in large transplant centers in France, Germany, and the United Kingdom. Cost data were collected from the health care payer's perspective. A Bayesian revision technique was applied to distinguish effectiveness of current management options for CMV infection vs. CMV disease, an aspect that is currently underreported in literature. RESULTS: CMV prophylaxis in liver transplant recipients is generally more cost-effective than preemptive and wait-and-treat strategies. In order of importance, changes in drug costs, drug efficacy, specificity of CMV testing, cost of hospitalization, probability of CMV relapse and baseline CMV risk are the most important factors influencing the cost-effectiveness. CONCLUSION: This model describes different strategies applied for management of CMV in liver transplant patients and is useful both for current decision making, optimal disease management, and assessment of future research targets.

Evaluación económica del tratamiento con ácido acetilsalicílico en dosis bajas en la prevención primaria de enfermedades cardiovasculares / Health Economic Evaluation of Low-Dose Acetylsalicylic Acid in the Primary Prevention of Cardiovascular Disease

Introducción y objetivos. El ácido acetilsalicílico (AAS) en dosis bajas es un tratamiento estándar en pacientes con antecedentes de enfermedades cardiovasculares (ECV); se discute su empleo en prevención primaria. Recientes estudios apoyan su uso en personas de alto riesgo y sin antecedentes de ECV. Se evaluó la repercusión económica del uso de AAS en la prevención primaria de ECV en España. Métodos. Se desarrolló un modelo para estimar la relación coste/efectividad del tratamiento con AAS a dosis bajas en la prevención primaria de ECV a los 10 años. Se estudiaron los costes directos desde la perspectiva del Sistema Nacional de Salud (SNS) español. Los resultados se expresaron como coste por años de vida ganados y por años de vida ajustados por calidad. Resultados. La administración de AAS en dosis bajas a personas con riesgo de enfermedad coronaria (EC) ≥ 15% a los 10 años produce un ahorro neto medio de 797 euros (intervalo de confianza [IC] del 95%, 263-1.331 euros), que empieza el primer año. A partir de un riesgo anual ≥ 0,24%, este tratamiento ahorra costes al SNS. El tratamiento con AAS a toda la población española con riesgo produciría un ahorro de 26,5 millones de euros en servicios sanitarios desde el primer año. Conclusiones. El tratamiento con AAS en dosis bajas de individuos con riesgo de EC ≥ 15% a los 10 años produciría un ahorro de costes significativo al SNS. Los análisis de sensibilidad prueban la robustez de los resultados (AU)

Introduction and objectives. Low-dose aspirin is standard treatment for patients with a history of cardiovascular disease. Its use in primary prevention is more controversial. However, recent studies also support the use of aspirin in high-risk individuals with no history of cardiovascular disease. This study investigated the health economic implications of using low-dose aspirin in the primary prevention of cardiovascular disease in Spain. Methods. A model was developed to predict the cost- effectiveness of low-dose aspirin in the primary prevention of cardiovascular disease over a period of 10 years. The direct costs used were those of the Spanish National Health Service (NHS). Results were expressed as cost per life-year gained and per quality-adjusted life- year gained. Results. Administering low-dose aspirin to an individual with a 10-year risk of coronary heart disease ≥15% resulted in an average net saving of e 797 (95% CI, e 263-1331) over the 10-year period, with savings starting in the first year. For an annual risk ≥0.24%, this form of treatment would reduce NHS costs. Treating all at-risk individuals in the Spanish population with aspirin would save e 26.5 million from the healthcare budget, starting in the first year. Conclusions. Administering low-dose aspirin to individuals with a 10-year risk of coronary heart disease ≥15% would result in significant cost savings for the Spanish NHS. Sensitivity analysis confirmed the robustness of these findings (AU)