Lung Cancer Screening with Low-Dose CT in Smokers: A Systematic Review and Meta-Analysis.

Lung cancer continues to be one of the main causes of cancer death in Europe. Low-dose computed tomography (LDCT) has shown high potential for screening of lung cancer in smokers, most recently in two European trials. The aim of this review was to assess lung cancer screening of smokers by LDCT with respect to clinical effectiveness, radiological procedures, quality of life, and changes in smoking behavior. We searched electronic databases in April 2020 for publications of randomized controlled trials (RCT) reporting on lung cancer and overall mortality, lung cancer morbidity, and harms of LDCT screening. A meta-analysis was performed to estimate effects on mortality. Forty-three publications on 10 RCTs were included. The meta-analysis of eight studies showed a statistically significant relative reduction of lung cancer mortality of 12% in the screening group (risk ratio = 0.88; 95% CI: 0.79-0.97). Between 4% and 24% of screening-LDCT scans were classified as positive, and 84-96% of them turned out to be false positive. The risk of overdiagnosis was estimated between 19% and 69% of diagnosed lung cancers. Lung cancer screening can reduce disease-specific mortality in (former) smokers when stringent requirements and quality standards for performance are met.

Five year trends (2008-2012) in cardiac implantable electrical device utilization in five European nations: a case study in cross-country comparisons using administrative databases.

Aims: Common methodologies for analysis of analogous data sets are needed for international comparisons of treatment and outcomes. This study tests using administrative hospital discharge (HD) databases in five European countries to investigate variation/trends in pacemaker (PM) and implantable cardioverter defibrillator (ICD) implant rates in terms of patient characteristics/management, device subtype, and initial implantation vs. replacement, and compares findings with existing literature and European Heart Rhythm Association (EHRA) reports. Methods and results: HD databases from 2008 to 2012 in Austria, England, Germany, Italy and Slovenia were interrogated to extract admissions (without patient identification) associated with PM and ICD implants and replacements, using direct cross-referencing of procedure codes and common methodology to compare aggregate data. 1 338 199 records revealed 212 952 PM and 62 567 ICD procedures/year on average for a 204.4 million combined population, a crude implant rate of about 104/100 000 inhabitants for PMs and 30.6 for ICDs. The first implant/replacement rate ratios were 81/24 (PMs) and 25/7 (ICDs). Rates have increased, with cardiac resynchronization therapy (CRT) subtypes for both devices rising dramatically. Significant between- and within-country variation persists in lengths of stay and rates (Germany highest, Slovenia lowest). Adjusting for age lessened differences for PM rates, scarcely affected ICDs. Male/female ratios remained stable at 56/44% (PMs) and 79/21% (ICDs). About 90% of patients were discharged to home; 85-100% were inpatient admissions. Conclusion: To aid in policymaking and track outcomes, HD administrative data provides a reliable, relatively cheap, methodology for tracking implant rates for PMs and ICDs across countries, as comparisons to EHRA data and the literature indicated.

Recommendations for primary studies evaluating therapeutic medical devices were identified and systematically reported through reviewing existing guidance.

OBJECTIVES: The aim of the study was to review existing recommendations on study design, conduct, analysis, and reporting for primary studies of therapeutic medical devices (TMDs) and the closely related field of interventional procedures. STUDY DESIGN AND SETTING: We performed a targeted literature review of publications with recommendations for study design, conduct, analysis, and reporting for primary studies of TMDs and related technologies. We combined an electronic database search with a systematic screening of tables of content of selected journals and scanning the reference lists of relevant articles. RESULTS: We identified 40 publications authored or commissioned primarily by regulators, health technology assessment agencies, and expert groups. We identified study designs of randomized clinical trials that specifically address the quick, incremental development of TMDs and provider and patient preferences. The importance of contextual factors for TMD interventions should be considered during the selection of patients, providers, and centers, as well as in data collection and analysis. We also identified guidance for the analysis and quantification of learning curves as well as for the design and analysis of large registries of high quality. CONCLUSION: The methodology to conduct primary research for TMDs should be disseminated to support improvement of the evidence base for health technology assessments.

Ten recommendations for assessing the comparative effectiveness of therapeutic medical devices: a targeted review and adaptation.

OBJECTIVES: The aim of this study was to review existing guidance on the methods for evaluation of the comparative effectiveness (CE) of therapeutic medical devices (TMDs) and develop recommendations for systematic reviews (SRs) of CE of TMDs as part of health technology assessments. STUDY DESIGN AND SETTING: We performed a targeted literature review of evaluation frameworks and recommendations for evaluation methods for TMDs and related technologies. An electronic database search was combined with systematic screening of tables of content of selected journals and scanning the reference lists of relevant papers. RESULTS: We identified a framework for SRs of complex interventions (FSRCIs) and three documents providing detailed methodology for TMD evaluation. We applied the FSRCIs to TMD evaluation taking into account the more complex composition of the intervention, its rapid, incremental development, as well as the dependency of treatment effects on contextual factors and user proficiency. In 10 recommendations, including a template for a logic model for TMD, we summarized relevant factors that should be systematically considered. CONCLUSION: The quality of SRs of CE assessments of TMDs can be improved by applying these recommendations. This also may require an increase of the quality of primary studies.

USING EXPERT OPINION IN HEALTH TECHNOLOGY ASSESSMENT: A GUIDELINE REVIEW.

OBJECTIVES: External experts can be consulted at different stages of an HTA. When using vague information sources, it is particularly important to plan, analyze, and report the information processing in a standardized and transparent way. Our objective was to search and analyze recommendations regarding where and how to include expert data in HTA. METHODS: We performed a systematic database search and screened the Internet pages of seventy-seven HTA organizations for guidelines, recommendations, and methods papers that address the inclusion of experts in HTA. Relevant documents were downloaded, and information was extracted in a standard form. Results were merged in tables and narrative evidence synthesis. RESULTS: From twenty-two HTA organizations, we included forty-two documents that consider the use of expert opinion in HTA. Nearly all documents mention experts in the step of preparation of the evidence report. Six documents address their role for priority setting of topics, fifteen for scoping, twelve for the appraisal of evidence and results, another twelve documents mention experts when considering the dissemination of HTA results. During the assessment step, experts are most often asked to amend the literature search or to provide expertise for special data analyses. Another issue for external experts is to appraise the HTA results and refer them back to a clinical and social context. Little is reported on methods of expert elicitation when their input substitutes study data. CONCLUSIONS: Despite existing recommendations on the use of expert opinion in HTA, common standards for elicitation are scarce in HTA guidelines.

Effects of a helium/oxygen mixture on individuals' lung function and metabolic cost during submaximal exercise for participants with obstructive lung diseases.

BACKGROUND: Helium/oxygen therapies have been studied as a means to reduce the symptoms of obstructive lung diseases with inconclusive results in clinical trials. To better understand this variability in results, an exploratory physiological study was performed comparing the effects of helium/oxygen mixture (78%/22%) to that of medical air. METHODS: The gas mixtures were administered to healthy, asthmatic, and chronic obstructive pulmonary disease (COPD) participants, both moderate and severe (6 participants in each disease group, a total of 30); at rest and during submaximal cycling exercise with equivalent work rates. Measurements of ventilatory parameters, forced spirometry, and ergospirometry were obtained. RESULTS: There was no statistical difference in ventilatory and cardiac responses to breathing helium/oxygen during submaximal exercise. For asthmatics, but not for the COPD participants, there was a statistically significant benefit in reduced metabolic cost, determined through measurement of oxygen uptake, for the same exercise work rate. However, the individual data show that there were a mixture of responders and nonresponders to helium/oxygen in all of the groups. CONCLUSION: The inconsistent response to helium/oxygen between individuals is perhaps the key drawback to the more effective and widespread use of helium/oxygen to increase exercise capacity and for other therapeutic applications.

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.

Oncotyrol--Center for Personalized Cancer Medicine: Methods and Applications of Health Technology Assessment and Outcomes Research.

BACKGROUND: The Oncotyrol - Center for Personalized Cancer Medicine is an international and interdisciplinary alliance combining research and commercial competencies to accelerate the development, evaluation and translation of personalized healthcare strategies in cancer. The philosophy of Oncotyrol is to collaborate with relevant stakeholders and advance knowledge "from bench to bedside to population and back". Oncotyrol is funded through the COMET Excellence Program by the Austrian government via the national Austrian Research Promotion Agency (FFG). This article focuses on the role of health technology assessment (HTA) and outcomes research in personalized cancer medicine in the context of Oncotyrol. METHODS: Oncotyrol, which currently comprises approximately 20 individual projects, has four research areas: Area 1: Biomarker and Drug Target Identification; Area 2: Assay Development and Drug Screening; Area 3: Innovative Therapies; Area 4: Health Technology Assessment and Bioinformatics. Area 4 translates the results from Areas 1 to 3 to populations and society and reports them back to Area 3 to inform clinical studies and guidelines, and to Areas 1 and 2 to guide further research and development. RESULTS: In a series of international expert workshops, the Oncotyrol International Expert Task Force for Personalized Cancer Medicine developed the Methodological Framework for Early Health Technology Assessment and Decision Modeling in Cancer and practical guidelines in this field. Further projects included applications in the fields of sequential treatment of patients with chronic myeloid leukemia (CML), benefit-harm and cost-effectiveness evaluation of prostate cancer screening, effectiveness and cost-effectiveness of multiple cervical cancer screening strategies, and benefits and cost-effectiveness of genomic test-based treatment strategies in breast cancer. CONCLUSION: An interdisciplinary setting as generated in Oncotyrol provides unique opportunities such as systematically coordinating lab and bench research, product development, clinical studies and decision science/HTA and transparent joint planning of research and development with a partnership of researchers, manufacturers and health policy decision makers. However, generating a joint research and legal framework with numerous partners from different sectors can be challenging, particularly in the starting period of such an endeavor. The journey to translational personalized medicine through multidisciplinary collaborations may still be long and difficult, but it is evident that it must be continued to turn vision into reality.

Health technology assessment of utilization, practice and ethical issues of self-pay services in the German ambulatory health care setting.

OBJECTIVES: The provision of self-pay medical services is common across health care systems, but understudied. According to the German Medical Association, such services should be medically necessary, recommended or at least justifiable, and requested by the patient. We investigated the empirical evidence regarding frequency and practice of self-pay services as well as related ethical, social, and legal issues (ELSI). METHODS: A systematic literature search in electronic databases and a structured internet search on stakeholder websites with qualitative and quantitative information synthesis. RESULTS: Of 1,345 references, we included 64 articles. Between 19 and 53 % of insured persons received self-pay service offers from their physician; 16-19 % actively requested such services. Intraocular pressure measurement was the most common service, followed by ultrasound investigations. There is a major discussion about ELSI in the context of individual health services. CONCLUSIONS: Self-pay services are common medical procedures in Germany. However, the empirical evidence is limited in quality and extent, even for the most frequently provided services. Transparency of their provision should be increased and independent evidence-based patient information should be supplied.

Individual health services.

BACKGROUND: The German statutory health insurance (GKV) reimburses all health care services that are deemed sufficient, appropriate, and efficient. According to the German Medical Association (BÄK), individual health services (IGeL) are services that are not under liability of the GKV, medically necessary or recommendable or at least justifiable. They have to be explicitly requested by the patient and have to be paid out of pocket. RESEARCH QUESTIONS: The following questions regarding IGeL in the outpatient health care of GKV insurants are addressed in the present report: What is the empirical evidence regarding offers, utilization, practice, acceptance, and the relation between physician and patient, as well as the economic relevance of IGeL?What ethical, social, and legal aspects are related to IGeL? FOR TWO OF THE MOST COMMON IGEL, THE SCREENING FOR GLAUCOMA AND THE SCREENING FOR OVARIAN AND ENDOMETRIAL CANCER BY VAGINAL ULTRASOUND (VUS), THE FOLLOWING QUESTIONS ARE ADDRESSED: What is the evidence for the clinical effectiveness?Are there sub-populations for whom screening might be beneficial? METHODS: The evaluation is divided into two parts. For the first part a systematic literature review of primary studies and publications concerning ethical, social and legal aspects is performed. In the second part, rapid assessments of the clinical effectiveness for the two examples, glaucoma and VUS screening, are prepared. Therefore, in a first step, HTA-reports and systematic reviews are searched, followed by a search for original studies published after the end of the research period of the most recent HTA-report included. RESULTS: 29 studies were included for the first question. Between 19 and 53% of GKV members receive IGeL offers, of which three-quarters are realised. 16 to 19% of the insurants ask actively for IGeL. Intraocular tension measurement is the most common single IGeL service, accounting for up to 40% of the offers. It is followed by ultrasound assessments with up to 25% of the offers. Cancer screening and blood or laboratory services are also frequent and represent a major proportion of the demand. The ethical, social, and legal aspects discussed in the context of IGeL concern eight subject areas: autonomous patient decisions versus obtrusion,commercialization of medicine, duty of patient information, benefit, evidence, and (quality) control, role and relation of physicians and patients,relation to the GKV, social inequality,formally correct performance. For glaucoma screening, no randomized controlled trial (RCT) is identified that shows a patient relevant benefit. For VUS three RCT are included. However, they do not yet present mortality data concerning screened and non-screened persons. VUS screening shows a high degree of over-diagnosis in turn leading to invasive interventions. To diagnose one invasive carcinoma, 30 to 35 surgical procedures are necessary. CONCLUSION: IGeL are a relevant factor in the German statutory health care system. To provide more transparency, the requests for evidence-based and independent patient information should be considered. Whether official positive and negative-lists could be an appropriate instrument to give guidance to patients and physicians, should be examined. Generally, IGeL must be seen in the broader context of the discussions about the future design and development of the German health care system.

Prognostic values of specific respiratory sounds for asthma in adolescents.

Childhood wheezing is a common condition associated with asthma, but the term is often misapplied. The present study aimed to investigate the prognostic values of specific respiratory sounds for asthma onset in adolescence. In a prospective study, six specific respiratory sounds were evaluated for their prediction of asthma. Parents were asked for respiratory sounds of their initially asthma-free children and to describe them in specified terms. Self-reported doctor-diagnosed asthma of 1,569 children aged 5 to 14 years from Germany was assessed at baseline and at follow-up for up to 12 years later. Except for 'ronchus' (17%), reported 'gasp' and 'whimper' had the highest positive predictive values of 15% and 11%, respectively. These sounds also showed the greatest increase in asthma incidence (odds ratio = 3.18; 95%CI, 1.46-6.94 and odds ratio = 2.09; 95%CI, 1.00-4.37). It could be shown that from six respiratory sounds, 'gasp' and 'whimper' were the expressions with the best prediction for asthma onset. This study suggests that parents can sensibly distinguish between respiratory sounds and that it is important to specify breathing sounds, as not all are good predictors for asthma.