Procedures and Criteria for the regulation of innovative non-medicinal technologies into the benefit catalogue of solidly financed health care insurances

Because great interest in an efficient range of effective medicinal innovations and achievements has arisen, many countries have introduced procedures to regulate the adoption of innovative non-medicinal technologies into the benefit catalogue of solidly financed health care insurances. With this as a background, this report will describe procedures for the adoption of innovative non-medicinal technologies by solidly financed health care insurances in Germany, England, Australia and Switzerland. This report was commissioned by the German Agency for Health Technology Assessment at the German Institute for Medical Documentation and Information

Coated stents to prevent restenosis in coronary heart disease

Background: In-stent-restenosis (ISR) is considered to be an essential limiting factor of stenting in coronary heart disease (CHD). The development of coated stents has raised expectations on substantial lowering restenosis after stenting with decreasing the rate of restenosis and a reduction in the rate of clinical events. Objectives: The present analysis addresses the questions on medical effectiveness and cost-effectiveness of the use of various coated stent types in CHD. Methods: The literature was searched in December 2004 in the most relevant medical and economic databases. The medical evaluation was conducted on the basis of published RCT. The data from the studies regarding various angiographic, sonographic and clinical endpoints were checked for methodical quality and summarised in meta-analyses. Within the scope of economic evaluation the primary studies were analysed and modelling was performed, applying clinical effect estimates from the meta-analyses of the medical evaluation and current estimates of German costs. Results: Medical evaluation: Ten different stenttypes were used in the included 26 RCT. The results for heparin, silicon-carbide, carbon and PTFE coated stenttypes could not reveal any significant differences between the medical effectiveness of coated and uncoated stents. The application of sirolimus, paclitaxel, everolimus and 7-hexanoyltaxol eluting stents showed a significant lower restenosis at 6-9 months with decrease in the rate of restenosis for polymer-based sirolimus, paclitaxel and 7-hexanoyltaxol eluting stents. In contrast, the use of gold-coated and actinomycin-D eluting stents was associated with a significantly higher restenosis. The polymer-based sirolimus and paclitaxel eluting stents also showed a significant and considerable reduction in the rate of repeated percutaneous revascularisations at 6-12 months (3.5% vs. 19.7%; p<0.0001, RR=0.19 [95%CI: 0.11; 0.33] and 3.5% vs. 12.2%; p<0.0001, RR=0.30 [95%CI: 0.20; 0.43]) and an equivalent reduction in the rate of combined events. The 7-hexanoyltaxol-eluting stents caused, however, a significant increase of stent thrombosis as well as of myocardial infarctions. Economic evaluation: The allocation to polymer-based sirolimus and paclitaxel eluting stents resulted in incremental costs (compared with uncoated stents) of approximately 1,421 € and 1,234 € per patient, taking in account expected revascularisations during the first year after implantation. The mean incremental cost-effectiveness-ratios per avoided revascularisation was 8,881 € and 13,711 €, respectively. The "break-even"-prices for these stenttypes in the used model were 707 € and 551 €, and the "break-even"-risks for ISR after stenting with uncoated stent, was 76% and 65%, respectively. The use of the other evaluated coated stents seems not to be cost-effective. Discussion: The absolute effects and cost savings for patient groups with a higher risk of restenosis could be considerably higher than for patient groups with a lower risk of restenosis. The transferability of the results from the present analysis to other (sub)-populations and technology modifications is limited. The direct comparability of the results for sirolimus and paclitaxel eluting stents is also restricted. Conclusions: From a medical point of view the use of polymer-based sirolimus or paclitaxel eluting stents can be recommended. The use of gold coated, 7-hexanoyltaxol and actinomycin-D eluting stents is in contrast not recommendable. From an economical point of view and on the basis of current stent prices the polymer-based eluting sirolimus and paclitaxel stents should primarily be recommended for patients with a higher risk of restenosis

Assessments tools for risk prediction of cardiovascular diseases

Scientific background: Cardiovascular diseases have an enormous epidemiological and economic importance. For the selection of persons with increased total cardiovascular risk for individual-targeted (e. g. drug-based) prevention interventions different risk prognosis instruments (equations, point scores and table charts) were derived from studies or databases. The transferability of these prognostic instruments on the populations not examined in these data sources as well as their comparability are not clear. Research questions: The evaluation addresses the questions on the existence of instruments for risk prediction of cardiovascular diseases, their transferability and comparability. Methods: A systematic literature search was performed in the medical electronic databases in April 2008 beginning from 2004 and was completed with a hand search. Publications on the prognostic instruments for cardiovascular diseases as well as publications addressing external validity and/or comparing prognostic instruments were included in the evaluation. Results: The systematic lierature search yielded 734 hits. Three systematic reviews, 38 publications with descriptions of prognostic instruments and 29 publications with data on the validity of the prognosis instruments were identified. Most risk prognosis instruments are based on the Framingham cohort of the USA. Only the PROCAM study is completely based on the German reference population. Almost all prognostic instruments use the variables sex, age, smoking, different parameters of the lipid status and of the blood pressure. Different cardiovascular events are considered to be an end parameter in the prognosis instruments. The time span for predicted events in the studies mostly comprises ten years.Data on calibration of the prognosis instruments (a quotient of the predicted by the observed risk) are presented in nearly half of the studies on the validation, however in no study from Germany. Only single studies find the levels of calibration between 0.9 and 1.1. Many studies on the transferability of the prognosis instruments show a value of the discrimination (correct differentiation of persons with different risk levels, best value 1.0) between 0.7 and 0.8, few studies between 0.8 and 0.9 and no study over 0.9. The studies addressing the discrimination of the prognostic instruments on the German population almost always find values between 0.7 and 0.8. The comparison of the validity of different risk prognosis instruments shows a trend for a better calibration and a better discrimination for the prognosis instruments examined on the derivation and/or validation cohorts of one of the compared prognostic instruments. Comparing the prognostic instruments on other cohorts, the newly derived Framingham prognostic instruments show a better discrimination in comparison with previously derived instruments. No studies exists comparing different prognostic instruments on the German population. Discussion: The geographic variance of the cardiovascular morbidity and mortality supposed to be the most important factor limiting the transferability of the prognostic instruments. An appropriate recalibration is considered to be an approach for the improvement of the transferability. Conclusions: The identified instruments for the risk prediction of cardiovascular diseases are insufficiently validated on the German population. Their use can lead to false risk estimation for a single person. Therefore, the existing prognostic instruments should be used for the informed decision-making and for the therapy selection in Germany only with critical caution

Interventions for enhancing medication compliance/adherence with benefits in treatment outcomes

Scientific background: Poor compliance or adherence in drug therapy can cause increased morbidity, mortality and enormous costs in the healthcare system (in Germany annually approximately 10 billion euros). Different methods are used for enhancing the compliance or adherence. Research questions: The evaluation addresses the questions about existence, efficacy, cost-benefit relation as well as ethical-social and juridical implications of strategies for enhancing compliance or adherence in drug therapy with concomitant improvements in treatment outcomes. Methods: A systematic literature search was conducted in the medical, also health economic relevant, literature databases in January 2007, beginning from 2002. Systematic reviews on the basis of (randomised controlled trials (RCT) concerning interventions to enhance compliance or adherence with regard to treatment outcomes as well as systematic reviews of health economic analyses were included in the evaluation. Additionally, it was also searched for publications which primarily considered ethical-social and juridical aspects of these interventions for the German context. Results: One systematic review with data for 57 RCT was included in the medical evaluation and one systematic review with data for six studies into the health economic evaluation. No publication primary concerning ethical-social or juridical implications could be identified. A significant positive effect on the treatment outcome was reported for 22 evaluated interventions. For many interventions the results can be classified as reliable: counseling with providing an information leaflet and compliance diary chart followed by phone consultation for helicobacter pylori positive patients, repeated counseling for patients with acute asthma symptoms, telephone calls to establish the level of compliance and to make recommendations based on that for the therapy of cardiovascular diseases, calls of an automated telephone system with phone counseling in problem cases for diabetics, different family based interventions including repeated family counseling, education and "culturally modified family therapy" in patients with schizophrenia, repeated "compliance therapy" sessions for patients with acute psychosis. For other interventions the results should be viewed with more concern (because of the poor methodical quality of the underlying studies). The effect size of the interventions can not be estimated from the available data. From the available data, no reliable results can be provided concerning the cost-benefit relation of these strategies. Discussion: Many of the reported studies had a poor reporting and methodological quality. The reliability of the conclusions of the studies is restricted because of methodical shortcomings. Efficacy and cost estimates determined in the health economic studies are not transferable to the current situation in Germany. It has been discussed recently that the compliance or adherence enhancing interventions can restrict the autonomy and the privacy of the patients. Conclusions: In drug therapy some compliance or adherence enhancing interventions with concomitant positive effect on the treatment outcome may be used. The cost-benefit relation of these interventions is to be estimated. Using these interventions the patient’s autonomy and privacy are to be restricted as few as possible

Percutaneous coronary intervention with optimal medical therapy vs. optimal medical therapy alone for patients with stable angina pectoris

Scientific background: Stable Angina Pectoris (AP) is a main syndrome of chronic coronary artery disease (CAD), a disease with enormous epidemiological and health economic relevance. Medical therapy and percutaneous coronary interventions (PCI) are the most important methods used in the treatment of chronic CAD. Research questions: The evaluation addresses questions on medical efficacy, incremental cost-effectiveness as well as ethic, social and legal aspects in the use of PCI in CAD patients in comparison to optimal medical therapy alone. Methods: A systematic literature search was conducted in June 2010 in the electronic databases (MEDLINE, EMBASE etc.) and was completed by a hand search. The medical analysis was initially based on systematic reviews of randomized controlled trials (RCT) and was followed by the evaluation of RCT with use of current optimal medical therapy. The results of the RCT were combined using meta-analysis. The strength and the applicability of the determined evidence were appraised. The health economic analysis was initially focused on the published studies. Additionally, a health economic modelling was performed with clinical assumptions derived from the conducted meta-analysis and economic assumptions derived from the German Diagnosis Related Groups 2011. Results: Seven systematic reviews (applicability of the evidence low) and three RCT with use of optimal medical therapy (applicability of the evidence for the endpoints AP and revascularisations moderate, for further endpoints high) were included in the medical analysis. The results from RCT are used as a base of the evaluation. The routine use of the PCI reduces the proportion of patients with AP attacks in the follow-up after one and after three years in comparison with optimal medical therapy alone (evidence strength moderate); however, this effect was not demonstrated in the follow-up after five years (evidence strength low). The difference in effect in the follow-up after four to five years was not found for the further investigated clinical endpoints: death, cardiac death, myocardial infarction and stroke (evidence strength high) as well as for severe heart failure (evidence strength moderate). Two studies were included in the health economic analysis. The costs estimations from these studies are not directly transferable to the corresponding costs in Germany. The average difference in the total costs for PCI in comparison with optimal medical therapy alone, which was calculated in the modelling, was found to be 4,217 Euro per patient. The incremental cost-effectiveness ratio per life-year of a patient with avoided AP attacks was estimated to be 24,805 Euro (evidence strength moderate). No publication was identified concerning ethical, social or legal aspects. Discussion: Important methodical problems of the studies are a lack of blinding of the patients and incomplete data for several endpoints in the follow-up. The determined incremental cost-effectiveness ratio per life-year of a patient with avoided AP attacks was appraised not to be cost-effective. Conclusions: From a medical point of view the routine use of PCI in addition to the optimal medicinal therapy in patients with stable AP can be recommended for the reduction of the proportion of patients with AP attacks after one year and after three years (recommendation degree weak). Otherwise, PCI is to be performed in patients with refractory or progressing AP despite of optimal medical therapy use; in this case PCI is expected to be applied in 27% to 30% of patients in five years. From the health economic view the routine use of PCI in addition to an optimal medical therapy in patients with stable AP cannot be recommended. No special considerations can be made concerning special ethical, social or legal aspects in the routine use of PCI in addition to optimal medical therapy in patients with stable AP

Specific immunotherapy (SIT) in the treatment of allergic rhinitis

Scientific background: Allergic rhinitis (AR) exhibits a prevalence of approx. 20% in Germany and causes enormous costs in the health care system. Specific immunotherapy (SIT) is considered to be the only potentially causal therapy for AR and mainly administered by two routes, subcutaneous (SCIT) and sublinguale (SLIT). SIT promises a reduction of symptoms and the need for medication in patients with AR. Research questions: The question arises, to what extent is SIT effective and cost effective in the treatment of AR and which ethical-social and legal aspects have to be considered regarding its application. Methods: The literature search was accomplished in the electronic data bases MEDLINE, EMBASE etc. in February 2008. The medical evaluation was based on systematic reviews of blinded, randomised controlled studies (RCT). The economic evaluation included health-economic studies on the basis of RCT. Additionally, it was also searched for publications explicitly addressing ethical-social and legal aspects of the use of SIT. Results: Medical evaluationTwo reviews on SCIT and three on SLIT were included in the medical evaluation. For the evaluation of SIT with grass pollen results for short and medium-term effects are considered from several studies, for SIT with other seasonal allergens (e. g. tree pollen) and with house dust mite allergens from clearly fewer studies and for SIT with other perennial allergens only from a few. The reviews report a significant reduction of the symptom and medication score in favour of SCIT with seasonal allergens and recognise the effectiveness at least for grass pollen allergens. Also for other seasonal allergens SCIT is appraised as effective. The reviews about SLIT determine a significant reduction of the symptom and the medication score in favour of SLIT vs. placebo in short and medium term follow-up in evaluations across all allergens. The subgroup analyses show a significant reduction of the symptom and medication score only in favour of SLIT with seasonal allergens. Health economic evaluationFour publications about two health economic studies are identified, one of these publications on Alutard-SQ® injections (SCIT) and three on GRAZAX® tablets (SLIT). The studies provide more (on Alutard-SQ®) or less (on GRAZAX®) robust information, but no evidence on cost effectiveness of these SIT administration forms in patients with AR. Discussion: The topic of the report is very broad, so that the evidence is summarised using systematic reviews. In particular the statistic heterogeneity of the studies found in the reviews considerably limits the strength of the findings. The included health economic studies show different methodical flaws, the largest potential bias is the projection of the magnitude of the medium-term clinical effects on the time period of nine years. Conclusions: The effectiveness of SIT in patients with AR is not equally proven for all SIT administration forms and allergens. For SCIT and SLIT with grass pollen allergens short and medium-term effectiveness can be regarded as proven. These therapy forms should be used if the indication is appropriate and if no contraindications are present. Also SCIT and SLIT with other seasonal allergens such as tree pollen allergens can be an effective treatment option, but used with a certain restraint due to insufficient data especially in the case of SLIT. For SIT with house dust mite allergens and further perennial allergens no consistent proof of effectiveness are to be determined from the available information. Further research addressing non-grass pollen-associated SIT, allergen and manufacturer specific evaluations as well as asthma prevention is needed. Due to the lack of evidence the use of SIT can not be seen proven as cost effective. To provide such evidence further health economic studies with a long term follow-up are needed. The informed consent of the patients is an important ethical requirement within the use of SIT

Arthroplasty register for Germany

Scientific background: The annual number of joint replacement operations in Germany is high. The introduction of an arthroplasty register promises an important contribution to the improvement of the quality of patient’s care. Research questions: The presented report addresses the questions on organization and functioning, benefits and cost-benefits as well as on legal, ethical and social aspects of the arthroplasty registers. Methods: A systematic literature search was conducted in September 2008 in the medical databases MEDLINE, EMBASE etc. and was complemented with a hand search. Documents describing arthroplasty registers and/or their relevance as well as papers on legal, ethical and social aspects of such registers were included in the evaluation. The most important information was extracted and analysed. Results: Data concerning 30 arthroplasty registers in 19 countries as well as one international arthroplasty register were identified. Most of the arthroplasty registers are maintained by national orthopedic societies, others by health authorities or by their cooperation. Mostly, registries are financially supported by governments and rarely by other sources.The participation of the orthopedists in the data collection process of the arthroplasty registry is voluntary in most countries. The consent of the patients is usually required. The unique patient identification is ensured in nearly all registers.Each data set consists of patient and clinic identification numbers, data on diagnosis, the performed intervention, the operation date and implanted prostheses. The use of clinical scores, patient-reported questionnaires and radiological documentation is rare. Methods for data documentation and transfer are paper form, electronic entry as well as scanning of the data using bar codes. The data are mostly being checked for their completeness and validity. Most registers offer results of the data evaluation to the treating orthopedists and/or hospitals, provide annual reports and publish scientific articles and/or presentations. The effects of the arthroplasty registers on clinical practice and on health political decisions in the time after the introduction of these registers are documented in some countries. The influence on cost savings for health services is also reported. Discussion: The most important legal and ethical aspect is the patient’s data protection and, therefore, the requirement of patient’s consent. The involvement of the physicians in the data collection process is a further organisational and legal challenge. The 100% data collection, which is the aim of the registers due to their definition, should not cause disadvantages for certain groups of patients.ConclusionThe arthroplasty registers have a large medical and health-economic potential. Aspects of the patient’s data protection and the guaranteed financial support of the registers should be clarified before the introduction of a register

Model simulation of seasonal growth of Fucus vesiculosus in its benthic community

Numerical models are a suitable tool to quantify impacts of predicted climate change on complex ecosystems but are rarely used to study effects on benthic macroalgal communities. Fucus vesiculosus L. is a habitat-forming macroalga in the Baltic Sea and alarming shifts from the perennial Fucus community to annual filamentous algae are reported. We developed a box model able to simulate the seasonal growth of the Baltic Fucus-grazer-epiphyte system. This required the implementation of two state variables for Fucus biomass in units of carbon (C) and nitrogen (N). Model equations describe relevant physiological and ecological processes, such as storage of C and N assimilates by Fucus, shading effects of epiphytes or grazing by herbivores on both Fucus and epiphytes, but with species-specific rates and preferences. Parametrizations of the model equations and required initial conditions were based on measured parameters and process rates in the near-natural Kiel Outdoor Benthocosm (KOB) experiments during the Biological Impacts of Ocean Acidification project. To validate the model, we compared simulation results with observations in the KOB experiment that lasted from April 2013 until March 2014 under ambient and climate-change scenarios, that is, increased atmospheric temperature and partial pressure of carbon dioxide. The model reproduced the magnitude and seasonal cycles of Fucus growth and other processes in the KOBs over 1 yr under different scenarios. Now having established the Fucus model, it will be possible to better highlight the actual threat of climate change to the Fucus community in the shallow nearshore waters of the Baltic Sea