[Immunotherapies in the German healthcare system : Economic aspects of established antibodies and recently available therapies]. / Immuntherapien im deutschen Gesundheitswesen : Ökonomische Aspekte etablierter Antikörper und neuerer Therapien.

In the German healthcare system, immunotherapies have been well established for years. Currently there are over 100 registrations of monoclonal antibodies (MABs). In recent years, new immunotherapeutic approaches became available, amongst them checkpoint inhibitors and CAR­T cells in oncology. Increasing expenditures of the German statutory health insurance (SHI) system are regarded with concerns. This article presents an overview of the development and status of prescriptions and sales of selected immunotherapeutics in Germany. Data from 2015-2019 were analyzed, primarily from the GKV-Arzneimittel-Schnellinformation (GAmSi) and the consultancy IQVIA.In the group of older MABs, such as immunosuppressive and antineoplastic agents, biosimilars led to a (temporary) increase of applications, but reimbursement amounts are decreasing. Instruments of the SHI system like drug agreements, reference prices, and individual discount contracts intervene as expenditure control. Checkpoint inhibitors clearly show increasing prescriptions and expenditures. Finally, the CAR­T cells are indeed very expensive treatments, but are currently not that important due to the limited number of applications. In addition, the exemption from VAT of 19% and the signed discount agreements between suppliers and sickness funds reduce the burden. In 2015 and 2019, the net expenditures on drugs and surgical dressings accounted for 17.2% of the total expenditures on benefits of the SHI system. Should the expenditures on drugs increase overproportionately in the future, the German SHI system will be able to counteract with already available or new instruments, supported by the legislator. Manufacturers and the SHI system should develop joint actions to achieve solutions for new treatment approaches.

[Checklist for the Development and Assessment of Cost-of-Illness Studies]. / Checkliste zur Erstellung und Bewertung von Krankheitskostenstudien.

BACKGROUND: Cost-of-illness (CoI) studies are important instruments for estimating the socioeconomic burden of specified diseases. CoI studies provide important information about the cost structure of a disease, the resulting research need, approaches to improve aspects of care and, monetary consequences from different perspectives. This information can be useful for healthcare research and health policy. Due to heterogeneity of available Cost-of-Illness studies, the working group 'Health Economics' of the German Network for Healthcare Research (DNVF) in accordance with the German Society for Health Economics (DGGÖ) developed an instrument for the planning, conduct and assessment of CoI studies. METHODS: The checklist was developed based on a systematic literature search of published national and international checklists as well as guidelines and recommendations for development and assessment of CoI studies and health economic evaluations. Structure and subject matter of the generic checklist was designed, approved and, finally, examined in a pretest by the working group. RESULTS: Based on the results of the literature search (n=2 454), 58 articles were used for the identification of relevant criteria for the checklist. With respect to the results of the pretest, 6 dimensions were included in the checklist: (i) general aspects, (ii) identification of resources, (iii) description and quantification of resource consumption, (iv) valuation of resources (v) analysis and presentation of results and (vi) discussion and conclusion. In total, the 6 dimensions were operationalized through 37 items. CONCLUSION: This checklist is an initial approach to improve transparency and understanding of CoI studies in terms of the extent, structure and development of the socioeconomic burden of diseases. The checklist supports the comparability of different studies and facilitates study conception.

[Follow up of the CoDiM-Study: Cost of diabetes mellitus 2000-2009]. / Fortschreibung der KoDiM-Studie: Kosten des Diabetes mellitus 2000-2009.

Cost of illness studies create transparency on the economic dimension of diseases. By now, the CoDiM study, based on administrative data of AOK Hesse und KV Hesse, identifies costs of people with diabetes and diabetes related excess costs in Germany for a period of 10 years. To date, additionally adjusted results are available by accounting for effects caused by inflation and ageing of the population. From 2000 to 2009 the number of treated patients with diabetes increased by 49 %, adjusted for age by 31 %. Mean cost of patients with diabetes and diabetes related excess costs per capita turned out to be relatively stable over the time period observed. The relation of cost per patient with diabetes to cost of patients without diabetes didn't change. Due to the increase of the number of treated patients with diabetes in the past 10 years, the total direct cost, dependant on the approach of calculation (adjusting or not for inflation and ageing effects), rose by 28 % to 70 %, the therein included diabetes excess cost by 24 % to 61 %.

Economic burden of vulvar and vaginal intraepithelial neoplasia: retrospective cost study at a German dysplasia centre.

BACKGROUND: Human papillomavirus is responsible for a variety of diseases including grade 2 and 3 vulvar and vaginal intraepithelial neoplasia. The aim of this study was to assess parts of the burden of the last diseases including treatment costs. The direct medical resource use and cost of surgery associated with neoplasia and related diagnostic procedures (statutory health insurance perspective) were estimated, as were the indirect costs (productivity losses) associated with surgical treatment and related gynaecology visits for diagnostic purposes. METHODS: Data from 1991-2008 were retrospectively collected from patient records of the outpatient unit of the Gynaecological Dysplasia Clinic, Heinrich Heine University, Dusseldorf, Germany. Two subgroups of patients were analysed descriptively: women undergoing one surgical procedure related to a diagnosis of vulvar and/or vaginal intraepithelial neoplasia, and women undergoing two or more surgical procedures. Target measures were per-capita medical resource consumption, direct medical cost and indirect cost. RESULTS: Of the 94 women analysed, 52 underwent one surgical intervention and 42 two or more interventions (mean of 3.0 interventions during the total period of analysis). Patients undergoing one surgical intervention accrued €881 in direct costs and €682 in indirect costs; patients undergoing more than one intervention accrued €2,605 in direct costs and €2,432 in indirect costs. CONCLUSIONS: The economic burden on German statutory health insurance funds and society induced by surgical interventions and related diagnostic procedures for grade 2/3 vulvar and vaginal neoplasia should not be underrated. The cost burden is one part of the overall burden attributable to human papillomavirus infections.

Economic evaluation of enoxaparin for anticoagulation in early cardioversion of persisting nonvalvular atrial fibrillation: a statutory health insurance perspective from Germany.

OBJECTIVE: To estimate, from the perspective of Statutory Health Insurance (SHI, third-party payer) in Germany, the economic consequences of using the subcutaneous low-molecular-weight heparin (LMWH) enoxaparin instead of intravenous unfractionated heparin followed by oral phenprocoumon (UFH/PPC) for anticoagulation in patients undergoing transesophageal echocardiography (TEE)-guided early electrical cardioversion (ECV) of persisting nonvalvular atrial fibrillation (AF) without intracardiac clot. DESIGN AND SETTING: The incremental cost for the enoxaparin-based regimen versus the UFH/PPC-based regimen was chosen as the target variable. A decision-analytic model considering the in- and outpatient sectors was used to quantify the target variable. Resource use during in- and outpatient treatment was taken from the Anticoagulation in Cardioversion using Enoxaparin (ACE) trial and from expert interviews with cardiologists in Germany in order to reflect the day-to-day conditions of clinical practice. Costs were given by SHI expenses for inpatient treatment and for medical services, drugs, disposables, and laboratory tests during outpatient treatment. These costs were determined by multiplying utilized resource items by the price or tariff of each item based on German healthcare regulations for the reference period of 2003/2004. According to the ACE trial, the evaluation encompassed 28 (26-30) treatment days with two consecutive phases. Phase I with 5 (3-12) days comprised diagnostics, start of anticoagulation, and ECV. Phase II with the remaining days consisted of continued anticoagulation and patient monitoring. The dosage of enoxaparin was 1 mg/kg bodyweight twice daily in treatment phase I followed by 40 mg twice daily with a bodyweight <65 kg or 60 mg twice daily with a BW > or =65 kg in treatment phase II. The daily dosages of UFH by continuous infusion and overlapping PPC were adjusted to an International Normalized Ratio of 2.0-3.0 in treatment phase I followed by 2.25mg PPC once daily in treatment phase II. Patients with any comorbidity and complication level (CCL) and those with low comorbidity and complications expected to occur in rare cases only (low-risk patients) were analyzed separately. In each base-case analysis, exclusively point estimates of all respective model parameters were applied. MAIN OUTCOME MEASURES AND RESULTS: There were savings of 339 euro and 579 euro per patient receiving the enoxaparin-based regimen versus the UFH/PPC-based regimen in the case of patients with any CCL and of low-risk patients, respectively (1 euro approximate, equals $US1.25; first quarter 2004 values). In comprehensive sensitivity analyzes, the robustness of the model and its results was shown. First, the impact of the model parameters on the target variable for each patient group was quantified in a deterministic model. Secondly, the dependency of the target variable on random variables was described for each patient group using Monte Carlo simulation. Irrespective of the patient group, the cost weight and the base rate of hospitals for inpatient ECV in phase I turned out to have the greatest impact on the savings obtained by the enoxaparin-based regimen. In the case of patients with any CCL, this impact was about 1.4-fold of that of the probability of enoxaparin patients undergoing outpatient ECV in phase I. In the case of low-risk patients, the impact of the cost weight and the base rate of hospitals for inpatient ECV in phase I was about 4.1-fold of that of the price of enoxaparin 60 mg prefilled syringes in the outpatient sector. In 79% and 93% of 10,000 simulated comparisons each versus the UFH/PPC-based regimen, there were savings obtained by the enoxaparin-based regimen in patients with any CCL and in low-risk patients, respectively. CONCLUSIONS: Results of this evaluation showed that an enoxaparin-based regimen for TEE-guided ECV of AF in patients without intracardiac clot offers SHI in Germany a considerable saving potential when used instead of an UFH/PPC-based regimen.

Cost effectiveness of enoxaparin as prophylaxis against venous thromboembolic complications in acutely ill medical inpatients: modelling study from the hospital perspective in Germany.

OBJECTIVE: To estimate, from the hospital perspective in Germany, the cost effectiveness of the low-molecular-weight heparin (LMWH) subcutaneous enoxaparin sodium 40 mg once daily (ENOX) relative to no pharmacological prophylaxis (NPP) and relative to subcutaneous unfractionated heparin (UFH) 5,000 IU three times daily (low-dose UFH [LDUFH]). Each is used in addition to elastic bandages/compression stockings and physiotherapy in the prevention of venous thromboembolic events (VTE) in immobilised acutely ill medical inpatients without impaired renal function or extremes of body weight. METHODS: The incremental cost-effectiveness ratios (ICERs) of the 'additional cost for ENOX per clinical VTE avoided versus NPP' and 'additional cost for ENOX per episode of major bleeding avoided versus LDUFH' were chosen as target variables. The target variables were quantified using a modelling approach based on the decision-tree technique. Resource use during thromboprophylaxis, diagnosis and treatment of VTEs, episode of major bleeding and secondary pneumonia after pulmonary embolism (PE) was collected from a hospital survey. Costs were exclusively those to hospitals incurred by staff expenses, drugs, devices, disposables, laboratory tests and equipment for diagnostic procedures. These costs were determined by multiplying utilised resource items by the price or tariff of each item as of the first quarter of 2003. Safety and efficacy values of the comparators were taken from the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) and the THE-PRINCE (THromboEmbolism-PRevention IN Cardiac or respiratory disease with Enoxaparin) trials and from a meta-analysis. The evaluation encompassed 8 (6-14) days of thromboprophylaxis plus time to treat VTE and episode of major bleeding in hospital. Point estimates of all model parameters were applied exclusively in the base-case analysis. RESULTS: There were incremental costs of euro 1,106 for ENOX per clinical VTE avoided versus NPP (1 euro approximately equals 1.07 US dollars; average of the first quarter of 2003). ENOX dominated LDUFH: cost savings of euro 55,825 were obtained and 7.7 episodes of major bleeding were avoided by ENOX compared with LDUFH, each per 1000 patients. In comprehensive sensitivity analyses, the robustness of the model and its results was shown. CONCLUSIONS: Results of this evaluation suggest that, in immobilised acutely ill medical inpatients, ENOX may offer hospitals in Germany a very cost-effective option for thromboprophylaxis compared with NPP and a cost-saving alternative compared with LDUFH.

Modelling cost effectiveness and cost utility of sequential DMARD therapy including leflunomide in rheumatoid arthritis in Germany: I. Selected DMARDs and patient-related costs.

OBJECTIVE: To quantify direct costs of medication and cost of illness (according to functional capacity) for patients with rheumatoid arthritis (RA) in Germany, allowing further use in a health economic evaluation of sequential therapy with disease-modifying antirheumatic drugs (DMARDs) in specialised, i.e. rheumatological, care in Germany. DESIGN AND SETTING: The analysis was conducted from the societal perspective in Germany using a modelling approach, which was based on secondary analysis of existing data and on data from a sample of 583 patients from the German rheumatological database of 1998. Functional capacity was defined by the Hannover Functional Ability Questionnaire (HFAQ) scores. Costs were calculated from resources utilised and patients' work capacity. Direct costs consisted of outpatient medical services, inpatient treatment, long-term care and rehabilitation treatment. Indirect costs incurred by sick leave and premature retirement were quantified according to the human-capital approach. MAIN OUTCOME MEASURES AND RESULTS: Average total direct costs (year 1998-2001 values) per patient per year for continuous treatment with the selected DMARDs comprising costs for drugs, monitoring and treatment of adverse drug reactions (ADRs) were highest for intramuscular gold (sodium aurothiomalate) [euro 2106 (euro 1 approximately equal to $US 0.91; average of the period from 2000 through 2001)] followed by leflunomide (euro 2010), azathioprine (euro 1878), sulfasalazine (euro 1190), oral methotrexate (euro 708), and lowest for the antimalarials chloroquine/hydroxychloroquine (euro 684). There were additional yearly costs for RA-related non-DMARD medication of euro 554 per patient, including management of ADRs. Mean cost of illness (year 1998 values) excluding medication cost amounted to euro 17,868 per RA patient per year. Annual costs increased with increasing disability, i.e. decreasing functional capacity, of RA patients from euro 6029 per patient with more than 94% of functional capacity to euro 28,509 per patient with <20% of functional capacity. In general, there was a predominance of indirect costs in each of the categories of functional capacity, ranging between 74% and 87% of total (direct and indirect) annual costs per RA patient. Annual direct costs increased from euro 811 to euro 7438 per patient with increasing disability. Inpatient treatment was the predominant component of direct costs. Patients in the worst category (<20%) of function experienced hospital costs that were 6.5 times higher than those of patients in the best category (>94%). CONCLUSIONS: On the basis of the data presented it can be concluded that the results of this investigation are typical for patients in rheumatological care in Germany and can therefore be used in a health economic analysis of different DMARD sequences aimed at changing disease progression over time.

Modelling cost effectiveness and cost utility of sequential DMARD therapy including leflunomide for rheumatoid arthritis in Germany: II. The contribution of leflunomide to efficiency.

OBJECTIVE: To estimate the 3-year incremental cost effectiveness and cost utility of introducing leflunomide into sequential therapy, consisting of the most frequently used disease-modifying antirheumatic drugs (DMARDs), for patients with rheumatoid arthritis in specialised, i.e. rheumatological, care in Germany. DESIGN AND SETTING: The analysis was conducted from the societal perspective in Germany using an existing 3-year simulation model, which was adapted to the German healthcare system after secondary analysis of relevant publications and data. DMARD sequences including leflunomide were compared with those excluding leflunomide. Costs comprised direct costs incurred by treatment and indirect costs incurred by loss of productivity (sick leave and premature retirement) of rheumatoid arthritis patients. Effectiveness parameters were given by response years gained (RYGs) according to the American College of Rheumatology (ACR) criteria for 20%, 50% and 70% improvement (ACR20/50/70RYGs) and by QALYs gained (QALYGs). Costs, effects and QALYs were discounted by 5% per annum. In the base-case analysis, average values of costs, response years and QALYs were applied. Costs were in 1998-2001 values (euro 1 approximately equal to $US 0.91, average of the period from the year 2000 through 2001). MAIN OUTCOME MEASURES AND RESULTS: After 3 years, adding leflunomide was less costly and more effective than the strategy excluding leflunomide when total (direct and indirect) costs were considered. There were savings of euro 271,777 and 8.1, 4.3, 5.1 and 4.9 ACR20RYGs, ACR50RYGs, ACR70RYGs and QALYGs per 100 patients, respectively, obtained through adding leflunomide. Focusing on direct costs, adding leflunomide was more costly and more effective compared with excluding leflunomide, with an incremental cost effectiveness of euro 5004 per ACR20RYG, euro 9535 per ACR50RYG, euro 7996 per ACR70RYG, and an incremental cost utility of euro8301 per QALYG, after 3 years. The robustness of the results was shown in comprehensive sensitivity analyses. In the analysis of extremes, different combinations of the limits of cost, effectiveness and utility parameters were investigated. Adding leflunomide to sequential DMARD therapy remained dominant in 79% of the possible cases, i.e. was less costly and more effective than the strategy excluding leflunomide. Focusing on direct costs, adding leflunomide became dominant in 29% and remained more costly and more effective in 50% of possible cases. CONCLUSIONS: Our analysis suggests, with its underlying data and assumptions, that having leflunomide as an additional option in a DMARD treatment sequence extends the time patients benefit from DMARD therapy at reasonable additional direct costs. Adding leflunomide may even be cost saving when total (direct and indirect) costs are considered. As data on DMARD effectiveness were extracted from the results of clinical trials, real-world data from observational studies would be needed to corroborate the findings of the present analysis.

Cost effectiveness of ramipril in patients at high risk for cardiovascular events : economic evaluation of the HOPE (Heart Outcomes Prevention Evaluation) study for Germany from the Statutory Health Insurance perspective.

BACKGROUND: In the HOPE (Heart Outcomes Prevention Evaluation) trial, ramipril (compared with placebo) significantly reduced cardiovascular death and all-cause mortality as well as the incidence of costly cardiovascular events, such as myocardial infarction, revascularisation, stroke, cardiac arrest, hospitalisation due to heart failure and worsening angina pectoris, new-onset diabetes mellitus and microvascular diabetic complications. OBJECTIVE: Data from the HOPE study were used in a cost-effectiveness analysis to determine the additional cost per life-year gained (LYG) when the ACE inhibitor ramipril was added to the current medication of patients at high risk for cardiovascular events. The aim was to establish the incremental cost-effectiveness ratio (ICER) of ramipril versus placebo from the perspective of the Statutory Health Insurance (SHI) provider in Germany, for both the study population as a whole and for the subgroup of patients with diabetes. DESIGN: A modelling approach was used, based on secondary analysis of published data and retrospective application of costs. In the base-case analysis, average case-related expenses of the SHI were applied and LYG were quantified using the average of the difference between the survival rates in the ramipril and placebo groups during the HOPE trial. LYG beyond the trial duration were estimated by the method of declining exponential approximation of life expectancy. RESULTS: After a treatment period of 4.5 years, the ICER of ramipril versus placebo was Euros 4074/LYG and Euros 2486/LYG (discounted at 5% per annum and in 1998-2002 values; Euro 1 approximately USD 0.88; first quarter 2002 values) for the HOPE study population as a whole and the subgroup of patients with diabetes, respectively. To test the model's robustness, the influence of the model variables on the results was quantified using a deterministic model, and a best-case/worst-case scenario analysis. The effect of random variables was investigated in a Monte Carlo simulation. The acquisition cost for ramipril had the greatest impact on the ICER of ramipril (2.2-fold greater than the impact of the number of LYG). In 95% of the 10,000 simulation steps, the ICER of ramipril after 4.5 years of treatment was between Euros 1290 and Euros 9005 per LYG for the entire HOPE study population and between Euros 290 and Euros 6115 per LYG in the diabetic subgroup. CONCLUSIONS: Results of this evaluation suggest that ramipril is likely to be cost effective in secondary prevention of cardiovascular events from the perspective of the SHI (third-party payer) in Germany. The estimated ICER of ramipril compares well with other ICERs of widely accepted treatments used for the management of cardiovascular diseases, such as HMG-CoA reductase inhibitors.