Utilization of innovative medical technologies in German inpatient care: does evidence matter?

BACKGROUND: The reimbursement of new technologies in inpatient care is not always linked to a requirement for evidence-based evaluation of patient benefit. In Germany, every new technology approved for market was until recently eligible for reimbursement in inpatient care unless explicitly excluded. The aim of this work was (1) to investigate the type of evidence that was available at the time of introduction of 25 innovative technologies and how this evidence evolved over time, and (2) to explore the relationship between clinical evidence and utilization for these technologies in German inpatient care. METHODS: This study combined different methods. A systematic search for evidence published between 2003 and 2017 was conducted in four bibliographic databases, clinical trial registries, resources for clinical guidelines, and health technology assessment-databases. Information was also collected on funding mechanisms and safety notices. Utilization was measured by hospital procedures captured in claims data. The body of evidence, funding and safety notices per technology were analyzed descriptively. The relationship between utilization and evidence was explored empirically using a multilevel regression analysis. RESULTS: The number of included publications per technology ranges from two to 498. For all technologies, non-comparative studies form the bulk of the evidence. The number of randomized controlled clinical trials per technology ranges from zero to 19. Some technologies were utilized for several years without an adequate evidence base. A relationship between evidence and utilization could be shown for several but not all technologies. CONCLUSIONS: This study reveals a mixed picture regarding the evidence available for new technologies, and the relationship between the development of evidence and the use of technologies over time. Although the influence of funding and safety notices requires further investigation, these results re-emphasize the need for strengthening market approval standards and HTA pathways as well as approaches such as coverage with evidence development.

Performance of serum neurofilament light chain in a wide spectrum of clinical courses of amyotrophic lateral sclerosis-a cross-sectional multicenter study.

BACKGROUND AND PURPOSE: The objective was to assess the performance of serum neurofilament light chain (sNfL) in amyotrophic lateral sclerosis (ALS) in a wide range of disease courses, in terms of progression, duration and tracheostomy invasive ventilation (TIV). METHODS: A prospective cross-sectional study at 12 ALS centers in Germany was performed. sNfL concentrations were age adjusted using sNfL Z scores expressing the number of standard deviations from the mean of a control reference database and correlated to ALS duration and ALS progression rate (ALS-PR), defined by the decline of the ALS Functional Rating Scale. RESULTS: In the total ALS cohort (n = 1378) the sNfL Z score was elevated (3.04; 2.46-3.43; 99.88th percentile). There was a strong correlation of sNfL Z score with ALS-PR (p < 0.001). In patients with long (5-10 years, n = 167) or very long ALS duration (>10 years, n = 94) the sNfL Z score was significantly lower compared to the typical ALS duration of <5 years (n = 1059) (p < 0.001). Furthermore, in patients with TIV, decreasing sNfL Z scores were found in correlation with TIV duration and ALS-PR (p = 0.002; p < 0.001). CONCLUSIONS: The finding of moderate sNfL elevation in patients with long ALS duration underlined the favorable prognosis of low sNfL. The strong correlation of sNfL Z score with ALS-PR strengthened its value as progression marker in clinical management and research. The lowering of sNfL in correlation with long TIV duration could reflect a reduction either in disease activity or in the neuroaxonal substrate of biomarker formation during the protracted course of ALS.

Neurofilament light-chain response during therapy with antisense oligonucleotide tofersen in SOD1-related ALS: Treatment experience in clinical practice.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1-ALS), the antisense oligonucleotide tofersen had been investigated in a phase III study (VALOR) and subsequently introduced in an expanded access program. In this study we assess neurofilament light chain (NfL) before and during tofersen treatment. METHODS: In six SOD1-ALS patients treated with tofersen at three specialized ALS centers in Germany, NfL in cerebrospinal fluid (CSF-NfL) and/or serum (sNfL) were investigated using the ALS Functional Rating Scale Revised (ALSFRS-R) and ALS progression rate (ALS-PR), defined by monthly decline of ALSFRS-R. RESULTS: Three of the six SOD1-ALS patients reported a negative family history. Three patients harbored a homozygous c.272A > C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS-PR <0.9), whereas one patient demonstrated rapidly progressing ALS (ALS-PR = 2.66). Mean treatment duration was 6.5 (range 5 to 8) months. In all patients, NfL decreased (mean CSF-NfL: -66%, range -52% to -86%; mean sNfL: -62%, range -36% to -84%). sNfL after 5 months of tofersen treatment was significantly reduced compared with the nearest pretreatment measurement (P = .017). ALS-PR decreased in two patients, whereas no changes in ALSFRS-R were observed in four participants who had very low ALS-PR or ALSFRS-R values before treatment. DISCUSSION: In this case series, the significant NfL decline after tofersen treatment confirmed its value as response biomarker in an expanded clinical spectrum of SOD1-ALS. Given the previously reported strong correlation between sNfL and ALS progression, the NfL treatment response supports the notion of tofersen having disease-modifying activity.

Exploring determinants and regional variation of diagnostic imaging utilization rates in German inpatient care.

INTRODUCTION: Germany ranks high concerning the per capita supply of computer tomographs (CT) and positron emission tomographs (PET) which may incentivize supply-induced use. Beyond that, international comparison shows high per capita examinations. However, misuse of diagnostic imaging may cause harm to patients and the health care system. The use of diagnostic imaging in Germany has been insufficiently studied so far. Therefore, the study aimed to determine the extent of regional differences as well as supply and demand side factors of per capita CT and PET examinations in German inpatient care. METHODS: Cartographic visualizations and a random intercept model controlling for the regional disease burden, ambulatory provided supply and demand, and population deprivation between 2010 and 2017 for CT and between 2016 and 2017 for PET were applied. For this purpose, the Nationwide hospital discharge data (DRG statistics), hospital structured quality reports, the National Association of Statutory Health Insurance Physicians, the Central Research Institute of Ambulatory Health Care in Germany, and the German Index of Socioeconomic Deprivation were used. RESULTS: We found a substantial regional variation of examination rates (-63 to +108% for CT and from -94 up to +847% for PET). Regarding PET, the supply structures have a significant impact on examinations per 1,000 inhabitants (28.46, p < .000). Both devices were used in correlation with the regional disease burden. Ambulatory and inpatient CT examination rates were positively associated. DISCUSSION: The regional differences identified are to some extent attributable to the regional burden of disease and thus warranted. Although the inpatient PET supply influences utilization rates, the direction of the effect should be investigated more closely for valid statements. The findings in terms of CT should be treated with caution. The cartographic distribution and examination rates indicate global overuse. The clear separation of inpatient and ambulatory sectors leads to misallocation of scarce resources, medically unnecessary multiple examinations, and capacity utilization problems. CONCLUSION: The results obtained have great potential for assessing and analyzing the adoption and rapid expansion of imaging technologies. Capacity utilization figures should be the focus of further research to assess utilization rates both economically and medically. Policy makers should address ongoing issues of operational and organizational separation of inpatient and ambulatory sectors in the German health care system.

Reasons for (not) choosing dental treatments-A qualitative study based on patients' perspective.

Oral health is increasingly seen as a public health challenge due to the remarkable prevalence of oral diseases worldwide, the impact on general health, and health consequences that can arise for individuals. Compared to other health services, oral health services are usually not fully covered by statutory health insurance, which is seen as one reason in decision-making on dental treatments. Nevertheless, patients' reasons for treatment decisions are not well understood although they can provide valuable insights. The objective of this study was to identify reasons of choice for dental treatments and to explore patients' view on cost coverage in Germany. We conducted four focus group interviews with a total of 27 participants. The interviews were audiotaped and transcribed verbatim. Data was analyzed performing conventional content analysis. As part of a qualitative analysis, subcategories and categories were formed from identified reasons using an inductive approach. Our study supports and expands research in exploring patients' decision-making on dental treatments. It highlights a variety of 53 reasons of choice for dental treatments from patients' perspective, split in two categories "health care service", and "dentist & dental office". First category includes reasons regarding dental care performance (subcategories: "preconditions", "treatment", "costs", and "outcomes"). Second category demonstrates reasons regarding dentists, office structures and processes (subcategories: "professional skills", "social skills", "office staff & equipment", and "office processes"). Reasons named "most important" by the participants are out-of-pocket payments, dentists' training, and a relationship of trust between patient and dentist. Although the participants use incentive measures to lower financial burden, several perceived challenges exist. Identified reasons for choosing dental treatments provide a basis for further studies to quantify the relevance of these reasons from patients' perspective. Based on this, the various reasons identified can be considered in future policies to improve patients' utilization behavior, which can range from improved information sources to increased incentive measures.

Cerebrospinal fluid biomarkers of disease activity and progression in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disease, and only modest disease-modifying strategies have been established to date. Numerous clinical trials have been conducted in the past years, but have been severely hampered by the wide-ranging heterogeneity of both the biological origins and clinical characteristics of the disease. Thus, reliable biomarkers of disease activity are urgently needed to stratify patients into homogenous groups with aligned disease trajectories to allow a more effective design of clinical trial. In this review, the most promising candidate biomarkers in the cerebrospinal fluid (CSF) of patients with ALS will be summarised. Correlations between biomarker levels and clinical outcome parameters are discussed, while highlighting potential pitfalls and intercorrelations of these clinical parameters. Several CSF molecules have shown potential as biomarkers of progression and prognosis, but large, international, multicentric and longitudinal studies are crucial for validation. A more standardised choice of clinical endpoints in these studies, as well as the application of individualised models of clinical progression, would allow the quantification of disease trajectories, thereby allowing a more accurate analysis of the clinical implications of candidate biomarkers. Additionally, a comparative analysis of several biomarkers and ideally the application of a multivariate analysis including comprehensive genotypic, phenotypic and clinical characteristics collectively contributing to biomarker levels in the CSF, could promote their verification. Thus, reliable prognostic markers and markers of disease activity may improve clinical trial design and patient management in the direction of precision medicine.

Adoption of large-scale medical equipment: the impact of competition in the German inpatient sector.

The availability of large-scale medical equipment such as computed tomography (CT), magnet resonance imaging (MRI) and positron emission tomography (PET) scanners has increased rapidly worldwide over the last decades. Among OECD countries, Germany ranks high according to the number of imaging technologies and their applications per inhabitant. In contrast to other countries, there is no active governmental planning of large-scale medical equipment. We therefore investigated whether and how the adoption and distribution of CT, MRI and PET scanners in the German inpatient sector is subject to competition. Using a linear-probability model, we additionally examined the impact of regional, hospital- and population-based factors. In summary, our results indicate that the adoption rate by hospital sites decreases with the number of other sites being already equipped with the respective device and their proximity. However, the effect presumably depends on the technologies' stage within the diffusion process. No influence regarding the amount of state subsidies could be identified. Furthermore, hospital size and university status strongly affect the adoption.

[Large-Scale Medical Equipment - An Analysis of Supply Structures 20 Years after the Abolition of Site Planning]. / Medizintechnische Großgeräte ­ Eine Analyse der Versorgungsstrukturen 20 Jahre nach Aufhebung der Standortplanung.

AIM: The aim of this study was to examine the supply structures of computer tomographs (CT) and positron emission tomographs (PET) 20 years after abolishing site planning of large-scale medical equipment in the German inpatient sector. METHODOLOGY: Cartographic analyses were used to visualize the inpatient supply with CT and PET between 2010 and 2017. Regional differences were investigated in relation to population and disease burden to identify potentially over- and under-served areas. RESULTS: Almost German-wide coverage was observed for CT. Only 0.3 percent of the population did not have access to a device within 30 minutes of driving distance. In contrast, larger segments of the population in extensive regions did not have timely access to PET. In addition, there was a high degree of regional variation in supply, which could not be explained either by population density or the disease burden of the region. CONCLUSION: The supply structures of large-scale medical equipment over decades without concrete regulatory interventions reveal regional variation. This is to be viewed critically from both an economic and a medical perspective. The extent to which strengthening competitive elements or cross-sectoral site planning can lead to a demand-oriented and efficient supply of large-scale medical equipment still needs to be investigated in more detail.

Implementation of innovative medical technologies in German inpatient care: patterns of utilization and evidence development.

BACKGROUND: Innovative medical technologies are commonly associated with positive expectations. At the time of their introduction into care, there is often little evidence available regarding their benefits and harms. Accordingly, some innovative medical technologies with a lack of evidence are used widely until or even though findings of adverse events emerge, while others with study results supporting their safety and effectiveness remain underused. This study aims at examining the diffusion patterns of innovative medical technologies in German inpatient care between 2005 and 2017 while simultaneously considering evidence development. METHODS: Based on a qualitatively derived typology and a quantitative clustering of the adoption curves, a representative sample of 21 technologies was selected for further evaluation. Published scientific evidence on efficacy/effectiveness and safety of the technologies was identified and extracted in a systematic approach. Derived from a two-dimensional classification according to the degree of utilization and availability of supportive evidence, the diffusion patterns were then assigned to the categories "Success" (widespread/positive), "Hazard" (widespread/negative), "Overadoption" (widespread/limited or none), "Underadoption" (cautious/positive), "Vigilance" (cautious/negative), and "Prudence" (cautious/limited or none). RESULTS: Overall, we found limited evidence on the examined technologies regarding both the quantity and quality of published randomized controlled trials. Thus, the categories "Prudence" and "Overadoption" together account for nearly three-quarters of the years evaluated, followed by "Success" with 17%. Even when evidence is available, the transfer of knowledge into practice appears to be inhibited. CONCLUSIONS: The successful implementation of safe and effective innovative medical technologies into practice requires substantial further efforts by policymakers to strengthen systematic knowledge generation and translation. Creating an environment that encourages the conduct of rigorous studies, promotes knowledge translation, and rewards innovative medical technologies according to their added value is a prerequisite for the diffusion of valuable health care.

Cerebrospinal Fluid Neurofilament Light Chain (NfL) Predicts Disease Aggressiveness in Amyotrophic Lateral Sclerosis: An Application of the D50 Disease Progression Model.

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder. As previous therapeutic trials in ALS have been severely hampered by patients' heterogeneity, the identification of biomarkers that reliably reflect disease progression represents a priority in ALS research. Here, we used the D50 disease progression model to investigate correlations between cerebrospinal fluid (CSF) neurofilament light chain (NfL) levels and disease aggressiveness. The D50 model quantifies individual disease trajectories for each ALS patient. The value D50 provides a unified measure of a patient's overall disease aggressiveness (defined as time taken in months to lose 50% of functionality). The relative D50 (rD50) reflects the individual disease covered and can be calculated for any time point in the disease course. We analyzed clinical data from a well-defined cohort of 156 patients with ALS. The concentration of NfL in CSF samples was measured at two different laboratories using the same procedure. Based on patients' individual D50 values, we defined subgroups with high (<20), intermediate (20-40), or low (>40) disease aggressiveness. NfL levels were compared between these subgroups via analysis of covariance, using an array of confounding factors: age, gender, clinical phenotype, frontotemporal dementia, rD50-derived disease phase, and analyzing laboratory. We found highly significant differences in NfL concentrations between all three D50 subgroups (p < 0.001), representing an increase of NfL levels with increasing disease aggressiveness. The conducted analysis of covariance showed that this correlation was independent of gender, disease phenotype, and phase; however, age, analyzing laboratory, and dementia significantly influenced NfL concentration. We could show that CSF NfL is independent of patients' disease covered at the time of sampling. The present study provides strong evidence for the potential of NfL to reflect disease aggressiveness in ALS and in addition proofed to remain at stable levels throughout the disease course. Implementation of CSF NfL as a potential read-out for future therapeutic trials in ALS is currently constrained by its demonstrated susceptibility to (pre-)analytical variations. Here we show that the D50 model enables the discovery of correlations between clinical characteristics and CSF analytes and can be recommended for future studies evaluating potential biomarkers.