Annette Conrads-Frank

Progression-free survival as a surrogate endpoint in advanced breast cancer

OBJECTIVES Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) for anthracycline (A) and taxane-based (T) chemotherapy in advanced breast cancer (ABC). Using trial-level, meta-analytic approaches, we evaluated PFS as a surrogate endpoint. METHODS A literature review identified randomized, controlled A and T trials for ABC. Progression-based endpoints were classified by prospective definitions. Treatment effects were derived as hazard ratios for PFS (HRPFS) and OS (HROS). Kappa statistic assessed overall agreement. A fixed-effects regression model was used to predict HROS from observed HRPFS. Cross-validation was performed. Sensitivity and subgroup analyses were performed for PFS definition, year of last patient recruitment, line of treatment, and constant rate assumption. RESULTS Sixteen A and fifteen T trials met inclusion criteria, producing seventeen A (n = 4,323) and seventeen T (n = 5,893) trial-arm pairs. Agreement (kappa statistic) between the direction of HROS and HRPFS was 0.71 for A (p = .0029) and 0.75 for T (p = .0028). While HRPFS was a statistically significant predictor of HROS for both A (p = .0019) and T (p = .012), the explained variances were 0.49 (A) and 0.35 (T). In cross-validation, 97 percent of the 95 percent prediction intervals crossed the equivalence line, and the direction of predicted HROS agreed with observed HROS in 82 percent (A) and 76 percent (T). Results were robust in sensitivity and subgroup analyses. CONCLUSIONS This meta-analysis suggests that the trial-level treatment effect on PFS is significantly associated with the trial-level treatment effect on OS. However, prediction of OS based on PFS is surrounded with uncertainty.

Long-term effectiveness and cost-effectiveness of screening for Hepatitis C virus infection.

BACKGROUND Hepatitis C virus (HCV) infection is an emerging problem in public health. In most countries, the majority of HCV infected people are yet undiagnosed. Early detection and treatment may result in better health outcomes and save costs by preventing future advanced liver disease. The evidence for long-term effectiveness and cost-effectiveness of HCV screening was systematically reviewed. METHODS We performed a systematic literature search on long-term health-economic effects of HCV screening and included Health Technology Assessment (HTA) reports, systematic reviews, long-term clinical trials, full health economic and decision-analytic modelling studies with a sufficiently long time horizon and patient-relevant long-term outcomes such as life-years gained (LYG) or quality-adjusted life years (QALY) gained. Economic results were converted to 2005 Euros. RESULTS Seven studies were included. Target population, HCV prevalence, study perspective, discount rate, screening and antiviral treatment mode varied. The incremental effectiveness of HCV screening and early treatment compared to no screening and standard care varied from 0.0004 to 0.066 LYG, and from 0.0001 to 0.072 QALY. Incremental cost-effectiveness and cost-utility ratios of HCV screening vs. no screening were 3900-243,700 euro/LYG and 18,300-1,151,000 euro/QALY. HCV screening seems to be cost-effective in populations with high HCV prevalence, but not in low HCV prevalence populations. CONCLUSIONS HCV screening and early treatment have the potential to improve average life-expectancy, but should focus on populations with elevated HCV prevalence to be cost-effective. Further research on the long-term health-economic impact of HCV screening when combined with appropriate monitoring strategies in different European health care systems is needed.

Long-term effectiveness and cost-effectiveness of antiviral treatment in hepatitis C.

Summary.  We systematically reviewed the evidence for long‐term effectiveness and cost‐effectiveness of antiviral treatment in patients with chronic hepatitis C. We performed a systematic literature search on the long‐term effectiveness and cost‐effectiveness of AVT in hepatitis C (1990–March 2007), and included health technology assessment (HTA) reports, systematic reviews, long‐term clinical trials, economic studies conducted alongside clinical trials and decision‐analytic modelling studies. All costs were converted to 2005€. Antiviral therapy with peginterferon plus ribavirin in treatment‐naïve patients with chronic hepatitis C was the most effective (3.6–4.7 life years gained [LYG]) treatment and was reasonably cost‐effective (cost‐saving to 84 700€/quality adjusted life years [QALY]) when compared to interferon plus ribavirin. Some results also suggest cost‐effectiveness (below 8400€/(QALY) of re‐treatment in nonresponders/relapsers. Results for patients with persistently normal alanine aminotransferase (ALT) levels or with special co‐morbidities (e.g. HIV) or risk profiles were rare. We conclude that antiviral therapy may prolong life, improve long‐term health‐related quality‐of‐life and be reasonably cost‐effective in treatment‐naïve patients with chronic hepatitis C as well as in former relapsers/nonresponders. Further research is needed in patients with specific co‐morbidities or risk profiles.

BiomarCaRE: rationale and design of the European BiomarCaRE project including 300,000 participants from 13 European countries

Biomarkers are considered as tools to enhance cardiovascular risk estimation. However, the value of biomarkers on risk estimation beyond European risk scores, their comparative impact among different European regions and their role towards personalised medicine remains uncertain. Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) is an European collaborative research project with the primary objective to assess the value of established and emerging biomarkers for cardiovascular risk prediction. BiomarCaRE integrates clinical and epidemiological biomarker research and commercial enterprises throughout Europe to combine innovation in biomarker discovery for cardiovascular disease prediction with consecutive validation of biomarker effectiveness in large, well-defined primary and secondary prevention cohorts including over 300,000 participants from 13 European countries. Results from this study will contribute to improved cardiovascular risk prediction across different European populations. The present publication describes the rationale and design of the BiomarCaRE project.

Decision-analytic evaluation of the clinical effectiveness and cost-effectiveness of management programmes in chronic heart failure

While management programmes (MPs) for chronic heart failure (CHF) are clinically effective, their cost‐effectiveness remains uncertain. Thus, this study sought to determine the cost‐effectiveness of MPs.

Decision-Analytic Models to Simulate Health Outcomes and Costs in Heart Failure: A Systematic Review

Chronic heart failure (CHF) is a critical public health issue with increasing effect on the healthcare budgets of developed countries. Various decisionanalytic modelling approaches exist to estimate the cost effectiveness of health technologies for CHF. We sought to systematically identify these models and describe their structures.We performed a systematic literature review in MEDLINE/PreMEDLINE, EMBASE, EconLit and the Cost-Effectiveness Analysis Registry using a combination of search terms for CHF and decision-analytic models. The inclusion criterion required ‘use of a mathematical model evaluating both costs and health consequences for CHF management strategies’. Studies that were only economic evaluations alongside a clinical trial or that were purely descriptive studies were excluded.We identified 34 modelling studies investigating different interventions including screening (n = 1), diagnostics (n = 1), pharmaceuticals (n = 15), devices (n = 13), disease management programmes (n = 3) and cardiac transplantation (n = 1) in CHF. The identified models primarily focused on middle-aged to elderly patients with stable but progressed heart failure with systolic left ventricular dysfunction. Modelling approaches varied substantially and included 27 Markov models, three discrete-event simulation models and four mathematical equation sets models; 19 studies reported QALYs. Three models were externally validated. In addition to a detailed description of study characteristics, the model structure and output, the manuscript also contains a synthesis and critical appraisal for each of the modelling approaches.Well designed decision models are available for the evaluation of different CHF health technologies. Most models depend on New York Heart Association (NYHA) classes or number of hospitalizations as proxy for disease severity and progression. As the diagnostics and biomarkers evolve, there is the hope for better intermediate endpoints for modelling disease progression as those that are currently in use all have limitations.

Modelling the cost effectiveness of treatments for Parkinson's disease: a methodological review.

The objective of this review was to assess models of cost effectiveness for Parkinson’s disease (PD) published after July 2002 and to derive recommendations for future modelling.A systematic literature search was performed in the databases PubMed, Current Contents, EMBASE, EconLit, the Cochrane Database of Systematic Reviews, and DARE (Database of Abstracts of Reviews of Effectiveness), NHS EED (Economic Evaluation Database) and HTA (Health Technology Assessment) of the UK NHS Centre for Review and Dissemination (July 2002 to March 2010). Only fully published studies using decision trees, Markov models, individual simulation models or sets of mathematical equations were included.Most of the 11 studies identified used Markov models (n = 9) and two employed were based on decision trees. Based on the Hoehn & Yahr (HY) scale, authors evaluated the cost effectiveness of drug treatments (n = 6), surgical approaches such as deep brain stimulation (n = 1) or striatal cell grafting (n = 1), and diagnostic procedures such as single photon emission computed tomography (SPECT) testing (n = 3) over a time horizon of 1 year to lifetime. Costs were adapted to address a societal and/or healthcare provider/ third-party payer perspective. All but one of the interventions investigated were considered cost effective or cost saving.Cost-effectiveness modelling in PD between 2003 and 2010 showed only minor improvement when compared with our earlier review of models published from 1998 up to 2003. Cost-effectiveness modelling recommendations were complied with to only a limited extent, leaving room for quality improvement. More advanced modelling approaches may, so far, be underrepresented, but may be used in the future, driven by the research question. Adverse events of treatment, co-morbidities or disease complications are not yet sufficiently included in the models to adequately represent clinical reality.

Health technology assessment of medical devices: What is different? An overview of three European projects.

BACKGROUND With the growing use and importance of health technology assessment (HTA) in decision making during recent years, health technology assessors, decision makers and stakeholders are confronted with methodological challenges due to specific characteristics of health technologies (e. g., pharmaceuticals, diagnostic tests, screening programs), their developmental environment, and their regulation process. Being aware of the necessity to use HTA as a policy instrument for sustainable health care systems in a regulatory environment of decentralized Conformité Européenne (CE) marking, the European Union (EU) is increasingly supporting the development of methods for the assessment of medical devices (MD) on different levels: within the scope of European research projects and within joint assessment activities of the member states of the European network for Health Technology Assessment (EUnetHTA). OBJECTIVE First, this article describes three projects: MedtecHTA-Methods for Health Technology Assessment of Medical Devices, a European Perspective Work Package 3 (WP3), Comparative Effectiveness of Medical Devices led by the University for Health Sciences, Medical Informatics and Technology (UMIT). Second, we discuss the experiences of the Ludwig Boltzmann Institute Health Technology Assessment (LBI HTA) with the joint production of rapid assessments of medical devices by several European HTA agencies within EUnetHTA. Third, a brief outline is given of the framework of joint methodological guideline elaboration by the EUnetHTA partner organizations because a guideline for therapeutic MD is also being developed here. METHODS We will describe aims, methods and some preliminary results of MedtecHTA and EUnetHTA Joint Action 2 Work Package 5 Strand B (WP5B) applying the HTA Core Model for Rapid Assessment for national adaptation and reporting, and give an overview of the development process of methodological guidelines within WP 7 of EUnetHTA Joint Action 2. RESULTS Based on a literature review in MedtecHTA WP3 incremental development, context dependency and the physical mode of action of MD were identified as those characteristics making therapeutic MD different from drugs with regard to evaluation methods. In addition, regulation does not stipulate clinical trials. These characteristics were also identified as challenges for the production of joint assessments of MD within the HTA network EUnetHTA. Furthermore, adequate timing of assessment production, the variety of involved manufacturers, the non-transparent regulation process of MD in Europe and the often poor evidence base pose a challenge to EUnetHTA assessors. As a consequence, processes and methods for the joint production of rapid assessments must be continuously adapted and improved. DISCUSSION Research on HTA methods for the assessment of MD tries to provide tools to deal with rapidly developing devices during evidence generation, dependence of clinical effectiveness of MD on user experience and context factors. There are also tools to integrate evidence from different sources adjusting for different levels of validity, but these methods are not established and need high epidemiological and statistical expertise. A framework for deciding whether additional evidence is needed to reduce uncertainty regarding safety, clinical effectiveness and cost-effectiveness will be adapted to MD. The whole process of evidence generation before and after market access has to be considered to provide an environment for conclusive HTA recommendations informing health care decision making. In Joint Action 2, EUnetHTA develops transparent processes for the early dialogue with stakeholders and fosters dissemination of appropriate HTA methods. In the case of MD, there are special accumulated needs for such efforts.

Cost-effectiveness of the sequential application of tyrosine kinase inhibitors for the treatment of chronic myeloid leukemia.

Several tyrosine kinase inhibitors (TKIs) are approved for chronic myeloid leukemia (CML) therapy. We evaluated the long-term cost-effectiveness of seven sequential therapy regimens for CML in Austria. A cost-effectiveness analysis was performed using a state-transition Markov model. As model parameters, we used published trial data, clinical, epidemiological and economic data from the Austrian CML registry and national databases. We performed a cohort simulation over a life-long time-horizon from a societal perspective. Nilotinib without second-line TKI yielded an incremental cost-utility ratio of 121 400 €/quality-adjusted life year (QALY) compared to imatinib without second-line TKI after imatinib failure. Imatinib followed by nilotinib after failure resulted in 131 100 €/QALY compared to nilotinib without second-line TKI. Nilotinib followed by dasatinib yielded 152 400 €/QALY compared to imatinib followed by nilotinib after failure. Remaining strategies were dominated. The sequential application of TKIs is standard-of-care, and thus, our analysis points toward imatinib followed by nilotinib as the most cost-effective strategy.

Modelling the Cost Effectiveness of Treatments for Parkinson’s Disease

The objective of this review was to assess models of cost effectiveness for Parkinson’s disease (PD) published after July 2002 and to derive recommendations for future modelling.A systematic literature search was performed in the databases PubMed, Current Contents, EMBASE, EconLit, the Cochrane Database of Systematic Reviews, and DARE (Database of Abstracts of Reviews of Effectiveness), NHS EED (Economic Evaluation Database) and HTA (Health Technology Assessment) of the UK NHS Centre for Review and Dissemination (July 2002 to March 2010). Only fully published studies using decision trees, Markov models, individual simulation models or sets of mathematical equations were included.Most of the 11 studies identified used Markov models (n = 9) and two employed were based on decision trees. Based on the Hoehn & Yahr (HY) scale, authors evaluated the cost effectiveness of drug treatments (n = 6), surgical approaches such as deep brain stimulation (n = 1) or striatal cell grafting (n = 1), and diagnostic procedures such as single photon emission computed tomography (SPECT) testing (n = 3) over a time horizon of 1 year to lifetime. Costs were adapted to address a societal and/or healthcare provider/ third-party payer perspective. All but one of the interventions investigated were considered cost effective or cost saving.Cost-effectiveness modelling in PD between 2003 and 2010 showed only minor improvement when compared with our earlier review of models published from 1998 up to 2003. Cost-effectiveness modelling recommendations were complied with to only a limited extent, leaving room for quality improvement. More advanced modelling approaches may, so far, be underrepresented, but may be used in the future, driven by the research question. Adverse events of treatment, co-morbidities or disease complications are not yet sufficiently included in the models to adequately represent clinical reality.