Time-dependent cost comparison and health economic impact analysis of second-line interventions for transplant-ineligible patients with relapsed or refractory diffuse large B cell lymphoma.

OBJECTIVES: Novel interventions (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tafasitamab-lenalidomide [Tafa-L], polatuzumab-rituximab-bendamustine [pola-BR]) improve clinical outcomes in second-line (2 L) treatment of transplant-ineligible patients with early relapse or refractory (R/R) diffuse large B cell lymphoma (DLBCL). The costs vary depending on the respective treatment regimen and the treatment duration, difficult comparability in reimbursement decisions. The objective was to analyze the health economic impacts of novel 2 L interventions and conventional immunochemotherapies (bendamustine-rituximab [BR], rituximab-gemcitabine-oxaliplatin [R-GemOx]) from a German healthcare payer's perspective as a function of treatment duration. METHODS: An economic model was developed to compare treatment costs of 2 L interventions depending on the treatment duration. Treatment duration was measured by progression-free survival (PFS), identified based on a systematic review. Total and average costs were calculated over 5 years to evaluate incremental costs at median PFS for each intervention. RESULTS: Average costs per month at median PFS ranged from €2846 (95% CI: 5067-1641) to €40 535 (95% CI: 91180-N/A) for BR and liso-cel, respectively. Incremental costs at the lowest median PFS (R-GemOx: 5.3 months) revealed -€664, €5560, €11 817, €53 145, and €67 745 for BR, Tafa-L, pola-BR, axi-cel, and liso-cel as compared to R-GemOx, respectively. CONCLUSIONS: Analyses uncovered a variation of incremental costs of 2 L transplant-ineligible DLBCL interventions as a function of time leading to amortization of high-priced interventions.

Cost-effectiveness analysis of transplant-ineligible relapsed or refractory diffuse large B-cell lymphoma treatment options-Experience of the efficiency frontier approach.

OBJECTIVES: The treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) changed remarkably since the European Medicines Agency-approved chimeric antigen receptor T-cell (CAR-T) therapies (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tisagenlecleucel [tisa-cel]) for the third-line onwards (3+L), and targeted therapies (polatuzumab vedotin-bendamustine-rituximab [pola-BR], tafasitamab-lenalidomide [Tafa-L]) for the second-line (2L) onwards. As associated rising treatment costs represent an economic burden, the cost-effectiveness of transplant-ineligible R/R DLBCL interventions was assessed from a German healthcare payer's perspective, using the efficiency frontier (EF) approach. METHODS: A systematic literature review was performed to determine the clinical benefit concerning median overall survival (OS) of bendamustine-rituximab (BR), rituximab-gemcitabine-oxaliplatin (R-GemOx), axi-cel, liso-cel, tisa-cel, pola-BR, and Tafa-L. First-year treatment costs (drug and medical services costs) were calculated. Results were merged on two-dimensional graphs illustrating 2L and 3+L EFs. RESULTS: Second-line EF is formed by BR (median OS 11.49 months, €23 958) and Tafa-L (45.7, €104 541), 3+L EF is formed by R-GemOx (12.0, €29 080), Tafa-L (15.5, €104 541), and axi-cel (18.69, €308 516). These interventions build the respective cost-effectiveness thresholds for novel interventions. CONCLUSIONS: Using the EF approach, the currently most cost-effective interventions (based on cost-effectiveness ratios) in the indication of R/R DLBCL were identified to guide international reimbursement decisions.

Health economic analysis of patients treated with isavuconazole in a German comprehensive cancer centre.

BACKGROUND: Invasive fungal diseases (IFD) are life-threatening and demand timely and appropriate treatment. Research showed that isavuconazole treatment positively affects clinical outcome and length of hospital stay (LOS). OBJECTIVES: The aim of this study was to assess the hospital costs of patients diagnosed with IFD and treated with isavuconazole using real-world data from a German cancer centre. PATIENTS/METHODS: Data and LOS collected from Jan-2016 to Jun-2021 at Department I of Internal Medicine, University Hospital Cologne were retrieved. Case-related resources consumed during the hospital stay across isavuconazole routes of administration (oral, parenteral, and mixed administration) were identified, quantified, valued and compared via a cost analysis that adopted the healthcare payer perspective. RESULTS: In total, 101 cases with isavuconazole treatment were identified (oral: n = 22, 21.8%; parenteral: n = 59, 58.4%; mixed: n = 20, 19.8%). Median total LOS was greater in the mixed group (46.5 days; p = .009). Median ICU LOS and ventilation duration were both longest in the parenteral-only group (16 days, p = .008; 224 h, p = .003). Invasive aspergillosis was the most frequent isavuconazole indication (n = 86, 85.2%). Average hospital costs were highest in the mixed group (€ 101,226). The median overall costs of cases treated with isavuconazole was € 52,050. CONCLUSIONS: Treating IFD is resource intensive, often requires intensive care and implies high rates of in-hospital mortality. Our study emphasises the high hospital treatment costs and thus the need for reimbursement systems to enable live-saving costly treatments.

Retrospective modelling of hospital bed capacities associated with the administration of remdesivir during the first wave of COVID-19 in a German metropolitan city.

OBJECTIVES: Internationally, healthcare systems are confronted by an ever-increasing scarcity of medical resources due to the ongoing novel coronavirus disease 2019 (COVID-19) pandemic. The aim of this study was to investigate the impact of remdesivir on the demand of hospital bed capacities for hospitalized COVID-19 patients and to evaluate the potentially created capacities for treating additional COVID-19 patients or elective treatments at the hospital. METHODS: An epidemiological model was developed that utilized the population of Cologne (Germany) during the first COVID-19 wave (first hospitalized patient-30 September 2020) to compare two scenarios: no administration of remdesivir (A) and the administration of remdesivir according to the EMA label (B). The results of the Adaptive COVID-19 Treatment Trial were used to evaluate the potential impact of remdesivir on hospital capacity. RESULTS: With the first recorded patient on 2 March 2020, a total of 576 COVID-19 hospitalized patients were detected during the first wave in Cologne. Comparing both scenarios (A versus B) of the model, the administration of remdesivir increased the number of discharges from 259 to 293 (+5.8%) and fewer patients needed ICU admission [214 versus 178 (-6.3%)]. In addition, the model estimated 20 fewer deaths (scenario B). Based on a reduced length of stay, 31.4 hospital beds (57.0 versus 25.6) could have been freed by administering remdesivir to eligible patients. This would have allowed either the treatment of an additional 730 COVID-19 patients or 660 elective treatments. CONCLUSIONS: In our model, remdesivir administration profoundly contributed to free hospital capacities in the metropolitan city Cologne in Germany.

A cost of illness study of COVID-19 patients and retrospective modelling of potential cost savings when administering remdesivir during the pandemic "first wave" in a German tertiary care hospital.

PURPOSE: First detected in China in 2019, the novel coronavirus disease (COVID-19) has rapidly spread globally. Since then, healthcare systems are exposed to major challenges due to scarce personnel and financial resources. Therefore, this analysis intended to examine treatment costs of COVID-19 inpatients in a German single centre during the first pandemic wave in 2020 from a healthcare payer perspective. Potential cost savings were assessed considering the administration of remdesivir according to the European Medicines Agency label. METHODS: A retrospective medical-chart review was conducted on COVID-19 patients treated at University Hospital Cologne, Germany. Patients were clustered according to an eight-category ordinal scale reflecting different levels of supplemental oxygen. Potential cost savings due to the administration of remdesivir were retrospectively modelled based on a reduced length of stay, as shown in the Adaptive COVID-19 Treatment Trial. RESULTS: 105 COVID-19 patients were identified. There was wide variability in the service data with median treatment costs from EUR 900 to EUR 53,000 per patient, depending on major diagnosis categories and clinical severity. No supplemental oxygen was needed in 40 patients (38.1%). Forty-three (41.0%) patients were treated in intensive-care units, and 30 (69.8%) received invasive ventilation. In our model, in-label administration of remdesivir would have resulted in costs savings of EUR 2100 per COVID-19 inpatient (excluding acquisition costs). CONCLUSION: We found that COVID-19 inpatients suffer from heterogeneous disease patterns with a variety of incurred G-DRG tariffs and treatment costs. Theoretically shown in the model, financial resources can be saved by the administration of remdesivir in eligible inpatients.

Health economic analysis of third-line interventions in diffuse large B-cell lymphomas in Germany: applying the efficiency frontier.

BACKGROUND: In the past decades, highly innovative treatments in the field of diffuse large B-cell lymphoma (DLBCL) became available in clinical practice. The aim of this study was to assess the cost-benefit relation of third-line interventions in DLBCL from a German payer perspective. METHODS: Clinical benefit of allogeneic stem cell transplantation (alloSCT), chimeric antigen receptor T cells therapy (CAR T) [tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel)] and best supportive care (BSC) was assessed in terms of median overall survival (median OS) derived from a systematic literature review in PubMed. Real-world treatment costs were retrieved from the university hospitals Cologne and Hamburg-Eppendorf. The cost-benefit relation was analysed using the efficiency frontier concept. RESULTS: Median OS varied from 6.3 months in BSC to 23.5 months in CAR T (axi-cel), while median real-world treatment costs ranged likewise widely from €26,918 in BSC to €340,458 in CAR T (axi-cel). Shown by the efficiency frontier, alloSCT and axi-cel were found as most efficient interventions. CONCLUSION: The efficiency frontier supports the pricing of innovative therapies, such as third-line interventions in DLBCL, in relation to appropriate comparators. Yet, studies with longer follow-up periods are needed to include studies with unreached median OS and to reflect experiences gained with CAR T in clinical practice.

Reimbursement of innovative pharmaceuticals in English and Spanish hospitals-The example of isavuconazole.

BACKGROUND: Kron et al (Mycoses, 64, 2021, 86) found cost savings for the use of the innovative pharmaceutical isavuconazole in the inpatient setting in Germany (Bismarck-based healthcare system). Little is known about the reimbursement of innovative pharmaceuticals in the inpatient setting of Beveridge-based healthcare systems. OBJECTIVES: The aim of this study was to evaluate the market access process and reimbursement of isavuconazole, exemplary for innovative pharmaceuticals, in England and Spain. PATIENTS/METHODS: Market access processes of both countries were described. Focussing on typical patient clusters for isavuconazole treatment, reimbursement data regarding inpatients with (i) allogeneic haematopoietic stem cell transplantation or (ii) acute myeloid leukaemia was considered. Data were publicly available and of high topicality (England 2020/2021, Spain 2018). Discounting and a currency conversion to Euro were applied. RESULTS: This study showed that market access processes of both countries are broadly similar. Further, full reimbursement of isavuconazole as an innovative pharmaceutical may lead to reduction in resource utilisation. Without medication costs, isavuconazole can thus result in cost savings for both patient clusters due to a reduction in length of stay. CONCLUSIONS: Expenses for innovative pharmaceuticals may be balanced or even lead to cost savings due to a reduction in length of stay. The latter contributes to a greater patient benefit. For both healthcare system, the analyses highlighted drugs' cost-effectiveness and assessing its added value into reimbursement decisions is highly relevant.

A budget impact analysis of bezlotoxumab versus standard of care antibiotics only in patients at high risk of CDI recurrence from a hospital management perspective in Germany.

BACKGROUND: Clostridioides difficile infection (CDI) is one of the leading nosocomial infections, resulting in increased hospital length of stay and additional treatment costs. Bezlotoxumab, the first monoclonal antibody against CDI, has an 1 A guideline recommendation for prevention of CDI, after randomized clinical trials demonstrated its superior efficacy vs. placebo. METHODS: The budget impact analysis at hand is focused on patients at high risk of CDI recurrence. Treatment with standard of care (SoC) + bezlotoxumab was compared with current SoC alone in the 10 most associated Diagnosis Related Groups to identify, analyze, and evaluate potential cost savings per case from the German hospital management perspective. Based on variation in days to rehospitalization, three different case consolidation scenarios were assessed: no case consolidation, case consolidation for the SoC + bezlotoxumab treatment arm only, and case consolidation for both treatment arms. RESULTS: On average, the budget impact amounted to € 508.56 [range: € 424.85 - € 642.19] for no case consolidation, € 470.50 [range: € 378.75 - € 601.77] for case consolidation in the SoC + bezlotoxumab treatment arm, and € 618.00 [range: € 557.40 - € 758.41] for case consolidation in both treatment arms. CONCLUSIONS: The study demonstrated administration of SoC + bezlotoxumab in patients at high risk of CDI recurrence is cost-saving from a hospital management perspective. Reduced length of stay in bezlotoxumab treated patients creates free spatial and personnel capacities for the treating hospital. Yet, a requirement for hospitals to administer bezlotoxumab is the previously made request for additional fees and a successful price negotiation.

Upconversion Nanocrystal Doped Polymer Fiber Thermometer.

In recent years, lanthanide-doped nanothermometers have been mainly used in thin films or dispersed in organic solvents. However, both approaches have disadvantages such as the short interaction lengths of the active material with the pump beam or complicated handling, which can directly affect the achievable temperature resolution. We investigated the usability of a polymer fiber doped with upconversion nanocrystals as a thermometer. The fiber was excited with a wavelength stabilized diode laser at a wavelength of 976 nm. Emission spectra were recorded in a temperature range from 10 to 35 ∘C and the thermal emission changes were measured. Additionally, the pump power was varied to study the effect of self-induced heating on the thermometer specifications. Our fiber sensor shows a maximal thermal sensitivity of 1.45%/K and the minimal thermal resolution is below 20 mK. These results demonstrate that polymer fibers doped with nanocrystals constitute an attractive alternative to conventional fluorescence thermometers, as they add a long pump interaction length while also being insensitive to strong electrical fields or inert to bio-chemical environments.

Towards Highly Efficient Polymer Fiber Laser Sources for Integrated Photonic Sensors.

Lab-on-a-Chip (LoC) devices combining microfluidic analyte provision with integrated optical analysis are highly desirable for several applications in biological or medical sciences. While the microfluidic approach is already broadly addressed, some work needs to be done regarding the integrated optics, especially provision of highly integrable laser sources. Polymer optical fiber (POF) lasers represent an alignment-free, rugged, and flexible technology platform. Additionally, POFs are intrinsically compatible to polymer microfluidic devices. Home-made Rhodamine B (RB)-doped POFs were characterized with experimental and numerical parameter studies on their lasing potential. High output energies of 1.65 mJ, high slope efficiencies of 56 % , and 50 % -lifetimes of ≥900 k shots were extracted from RB:POFs. Furthermore, RB:POFs show broad spectral tunability over several tens of nanometers. A route to optimize polymer fiber lasers is revealed, providing functionality for a broad range of LoC devices. Spectral tunability, high efficiencies, and output energies enable a broad field of LoC applications.

How to optimize the CAR-T Cell therapy process? A group concept mapping analysis of preconditions for a frictionless process from a German multistakeholder perspective.

Introduction: Treatment with chimeric antigen receptor T (CAR-T) cells involves a large number of interdisciplinary stakeholders and is associated with complex processes ranging from patient-specific production to follow-up care. Due to the complexity, maximum process optimization is required in order to avoid efficiency losses. This study aimed at systematically determining the preconditions for a frictionless flow of the CAR-T process by surveying the stakeholders involved. Methods: A Group Concept Mapping (GCM) analysis, a mixed-methods participatory research, was conducted. CAR-T experts from different professional backgrounds went through three steps: 1) Brainstorming relevant aspects (statements) for a frictionless process, 2) Sorting the collected statements based on their similarity, and 3) Rating the importance and feasibility of each statement. A cluster map reflecting the overarching topics was derived, and mean ratings per statement and cluster were calculated. Results: Overall, 20 CAR-T experts participated. A total of 80 statements were collected, resulting in a map of the following 10 clusters (mean importance/feasibility): Information for patients and physicians (4.16/3.77), Supportive network (4.03/3.53), Eligibility of patients (4.41/3.63), Evidence, transparency and communication (4.01/3.33), Paperwork (4.1/2.52), Interface with pharmaceutical manufacturer (4.03/2.85), Reimbursement (4.29/2.31), Quality Management (4.17/3.18), Infrastructure of CAR-T clinics (4.1/2.93), and Patient-oriented processes (4.46/3.32). Discussion: The 80 statements underlined the complex and manifold nature of the CAR-T treatment process. Our results reflect the first step in overcoming hurdles: identifying potential hurdles and required preconditions. Decision-makers and stakeholders can use the results to derive strategies and measures to further promote a frictionless process.

Health-economic modelling of cost savings due to the use of rezafungin based on a German cost-of-illness study of candidiasis.

Objective: Candida species are responsible for fungal diseases and the development of nosocomial bloodstream infections. Treatment is resource-intensive and economically challenging for healthcare systems. Cost analyses of drugs against candidiasis, such as rezafungin, are thus of great interest to healthcare payers. Methods: We conducted a cost-of-illness study of patients with Candida infections based on real-word data of the Department I of Internal Medicine, University Hospital Cologne (Germany) between 2016 and 2021. Health-economic parameters were analysed to describe the economic impact of Candida infections. Potential cost savings due to the administration of rezafungin were modelled for patients with invasive candidiasis or candidaemia based on a 5 day reduction of ICU length of stay (LOS) shown by the STRIVE study. Results: We found 724 cases (652 patients) with Candida infections, of which 61% received ICU treatment (n = 442) and 29% were mechanically ventilated (n = 207). Twenty-six percent died during hospitalization (n = 185). Median LOS was 25 and 15 days, on normal wards and ICU, respectively. Median total treatment costs per case accounted for €22 820. Based on the ICU LOS reduction, the retrospective model showed a median cost-saving potential of €7175 per hospital case with invasive candidiasis or candidaemia. Accumulated cost savings for 37 patients of €283 335 were found. Conclusions: Treatment of candidiasis is cost intensive due to increased hospital LOS. The ICU LOS reduction rezafungin showed in STRIVE would lead to sustainable cost savings.

Last Resort Antibiotics Costs and Reimbursement Analysis of Real-Life ICU Patients with Pneumonia Caused by Multidrug-Resistant Gram-Negative Bacteria in Germany.

Multidrug-resistant Gram-negative bacteria (MDR-GNB) cause serious infections and aggravate disease progression. Last resort antibiotics are effective against MDR-GNB and are reimbursed by flat rates based on German diagnosis-related groups (G-DRG). From a hospital management perspective, this analysis compared hospital reimbursement for last resort antibiotics with their acquisition costs to outline potential funding gaps. Retrospective analyses based on medical charts and real-life reimbursement data included patients with pneumonia due to MDR-GNB treated in intensive care units (ICU) of a German tertiary care hospital (University Hospital Cologne) between January 2017 and December 2020. Drug-associated hospital reimbursement of G-DRG was compared with drug acquisition costs based on preliminarily approved last resort antibiotics (cefiderocol, ceftazidime-avibactam, ceftolozane-tazobactam, and imipenem-cilastatin-relebactam) according to label. Funding gaps were determined for the treatment of Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii, and mixed infections, respectively. Most of the 31 patients were infected with Enterobacterales (n = 15; 48.4%) and P. aeruginosa (n = 13; 41.9%). Drug-associated G-DRG reimbursement varied from 44.50 EUR (mixed infection of P. aeruginosa and Enterobacterales) to 2265.27 EUR (P. aeruginosa; mixed infection of P. aeruginosa and Enterobacterales). Drug acquisition costs ranged from 3284.40 EUR in ceftazidime-avibactam (minimum duration) to 15,827.01 EUR for imipenem-cilastatin-relebactam (maximum duration). Underfunding was found for all MDR-GNB, reaching from 1019.13 EUR (P. aeruginosa; mixed infection of P. aeruginosa and Enterobacterales) to 14,591.24 EUR (Enterobacterales). This analysis revealed the underfunding of last resort antibiotics in German hospital treatment. Insufficient reimbursement implies less research in this field, leading to a more frequent use of inappropriate antibiotics. The cycle closes as this contributes to the development of multi-drug resistant bacteria.

Economic Impact of the Introduction of Outpatient Medical Specialist Care (ASV) of Gastrointestinal Cancer Patients from a German Hospital Management Perspective.

INTRODUCTION: The treatment of cancer patients in Germany is characterized by sectoral separation of the in- and outpatient care accompanied by 2 separate reimbursement systems. By introducing the Guideline of Outpatient Medical Specialist Care in accordance with §116b SGB V (ASV) in 2014, the German legislation empowers office-based physicians and hospitals to jointly provide medical care in the ambulatory setting. METHODS: A 1-year period each before and after the introduction of ASV was compared by means of data from the Center for Integrated Oncology Cologne at the University Hospital of Cologne. Only adults with a reliable diagnosis of gastrointestinal tumor (GIT) were considered. RESULTS: Overall, 1,872 cases were considered in the analysis showing significant (p < 0.001) higher median values of revenues across ICD-subgroups for ASV (EUR 427.46) compared to Ambulatory Treatments in Hospitals (EUR 234.21). The exemplary analysis of revenues in neoplasms of the pancreas shows EUR 173.69 on average which are only invoiceable through ASV: flat rate incl. surcharges (EUR 117.79; 68%), structure lump sum (EUR 29.49; 17%), positron-emission tomography (PET)/CT (EUR 13.53; 18%), and ASV consultation hour (EUR 12.89; 7%). DISCUSSION/CONCLUSION: ASV leads to significant higher revenues across different ICD-subgroups for patients suffering from severe GIT. The collaboration of hospital and office-based physicians ensures patient-centered care with accumulated expertise and avoidance of double examinations. Thus, the inclusion of additional services in the Uniform Value Scale (invoiceable for ASV) is legitimated and enables cost-covering care for the involved parties.

Homogeneous Distribution of Polymerizable Coumarin Dyes for Active Few Mode POF.

For most kinds of active polymer optical fibers, a homogeneous distribution of dye molecules over the entire fiber length and cross section is required. In this study, chemical bonding of dyes to poly(methyl methacrylate) (PMMA) by copolymerization is achieved within the polymerization process instead of dissolving the dyes in the monomers. In combination with an improved fabrication mechanism, this leads to homogeneous dye distribution within the preforms. A method for proving the integration of the dyes into the polymer chains has been developed using high-performance liquid chromatography (HPLC) and size exclusion chromatography (SEC). Prestructured core-cladding preforms with dye-doped poly(cylohexyl methacrylate-co-methyl methacrylate)-core have been prepared with the Teflon string technique and were heat-drawn to few mode fibers.

Characterization of Double-Doped Polymer Optical Fibers as Luminescent Solar Concentrators.

This work reports on a diameter dependence analysis of the performance as luminescent solar concentrators of three self-fabricated polymer optical fibers (POFs) doped with a hybrid combination of dopants. The works carried out include the design and self-fabrication of the different diameter fibers; an experimental analysis of the output power, of the output irradiance and of the fluorescent fiber solar concentrator efficiency; a comparison of the experimental results with a theoretical model; a study of the performance of all the fibers under different simulated lighting conditions; and a calculation of the active fiber length of each of the samples, all of them as a function of the fiber core diameter. To the best of our knowledge, this paper reports the first analysis of the influence of the POF diameter for luminescent solar concentration applications. The results obtained offer a general perspective on the optimal design of solar energy concentrating systems based on doped POFs and pave the way for the implementation of cost-effective solar energy concentrating devices.

Thermal skyrmion diffusion used in a reshuffler device.

Magnetic skyrmions in thin films can be efficiently displaced with high speed by using spin-transfer torques1,2 and spin-orbit torques3-5 at low current densities. Although this favourable combination of properties has raised expectations for using skyrmions in devices6,7, only a few publications have studied the thermal effects on the skyrmion dynamics8-10. However, thermally induced skyrmion dynamics can be used for applications11 such as unconventional computing approaches12, as they have been predicted to be useful for probabilistic computing devices13. In our work, we uncover thermal diffusive skyrmion dynamics by a combined experimental and numerical study. We probed the dynamics of magnetic skyrmions in a specially tailored low-pinning multilayer material. The observed thermally excited skyrmion motion dominates the dynamics. Analysing the diffusion as a function of temperature, we found an exponential dependence, which we confirmed by means of numerical simulations. The diffusion of skyrmions was further used in a signal reshuffling device as part of a skyrmion-based probabilistic computing architecture. Owing to its inherent two-dimensional texture, the observation of a diffusive motion of skyrmions in thin-film systems may also yield insights in soft-matter-like characteristics (for example, studies of fluctuation theorems, thermally induced roughening and so on), which thus makes it highly desirable to realize and study thermal effects in experimentally accessible skyrmion systems.