INTRODUCTION:Frailty is associated with negative health outcomes in geriatric patients. A large proportion of frail patients is affected by polypharmacy, which in turn may be a possible cause of frailty. The cluster randomised controlled COFRAIL trial investigated the effects of family conferences to improve the care of frail patients. Deprescribing and communication about prioritising health goals between patients, relatives and general practitioners were key components of the intervention. An accompanying process evaluation was conducted to investigate whether the study intervention was implemented as intended and to describe the experiences of the target groups. METHODS:The process evaluation took place between February 2019 and October 2021 and followed international guidelines. Process parameters were collected using study documentation, standardised questionnaires and guided telephone interviews with a convenience sample of patients, relatives and general practitioners. Quantitative data were analysed descriptively, qualitative data through content analysis. RESULTS:Almost all general practitioners in the intervention group completed both mandatory trainings. Overall, 68% of the patients took part in all three planned family conferences, 85% in at least two. Patients, relatives and general practitioners reported positive experiences with the family conferences. Patients and relatives felt involved in the decision-making process and had predominantly no concerns when medication was discontinued. Only a few general practitioners considered the implementation of family conferences in regular care to be impractical. A supportive pharmacological hotline was not utilised frequently by the general practitioners. Due to the SARS-CoV-2 pandemic, some study procedures were adapted but did not have any negative impact. CONCLUSIONS:While the COFRAIL study did not achieve its primary goals, we identified no major barriers in the implementation of the intervention programme. Overall, the target groups experienced the approach of family conferences positively. However, the process evaluation provides valuable lessons for designing and implementing similar interventions in the future.

Effects of antihypertensive therapy are estimated in clinical trials. There is a need to prioritize the endpoints according to patients' preferences. 26 patients from two regions of Germany rated in 2019 their preferences regarding the importance of various endpoints of hypertension treatment (Mortality, Myocardial infarction, Stroke, Heart failure, and subdivided Adverse events) by a pairwise comparison of individual endpoints. Analytic Hierarchy Process (AHP), a multi-criteria decision analysis method was used to generate relative weights for each endpoint. The robustness of the results was defined by means of consistency. The elicitation yielded the following aggregated group weights: Stroke 0.320, Mortality 0.297, Myocardial infarction 0.202, Heart failure 0.119, and Adverse events 0.062, subdivided in Dyspnea, Pain, Edema, and Cough. The overall consistency reached for efficacy endpoints a consistency ratio below 0.1 (safety endpoints = 0.04) without exceeding established limits. In all sensitivity analyses but one, no rank reversal was observed, and Stroke was rated highest. Individual weights varied extensively. Some participants weighted Mortality (0.021-0.686) higher than Stroke (0.078-0.615) and Heart failure (0,021-0,469) higher than Myocardial infarction (0,047-0.431). Individual inconsistency exceeded the limits in almost half of the cases, with gender, therapy duration, and therapeutic scheme being explaining variables for inconsistency within binary logistic regression models. AHP can be used to obtain preferences of patients with primary hypertension for effectiveness and safety endpoints. Preference elicitation could provide important information for drug assessment (group weights) and shared decision-making (individual weights) following the concept of patient-centeredness at system and patient level.

Although Germany and France implement ordinal scaling when assessing medicines and follow a relative effectiveness approach, there are procedural and methodological differences. All G-BA and HAS decisions from 2011 to March 2023 were compared after assigning corresponding subgroups to harmonized added benefit categories. Descriptive statistics and dichotomous and ordinal agreement analyses by (weighted) Cohen’s Kappa were performed for procedures and subgroups. Logistic regression was calculated to identify explanatory variables for (dis-)agreement. 475 G-BA and 465 HAS identified decisions led to 907 considered subgroup-pairs. G-BA granted an added benefit in 59

BackgroundHypertension is a major risk factor for fatal and nonfatal cerebrovascular and cardiovascular events. Poor treatment adherence, a key measure impeding successful treatment, can be improved by incorporating patient preferences. We aimed to identify patient preferences for hypertension treatment outcomes by performing a quantitative exploratory field study using the analytic hierarchy process (AHP). We also explored the associations between patient preferences with prior cardiovascular and cerebrovascular events, sociodemographic factors, and health-related quality of life (HRQoL).MethodsWe quantified preferred outcomes by pairwise comparisons among individuals with hypertension, recruited in secondary and tertiary care settings. Individual weights were calculated using the eigenvector method. HRQoL was assessed via the EQ-5D-5L instrument, including its visual analogue scale.ResultsData from 263 participants revealed that stroke (weight: 0.271) and death (0.270) were equally prioritized as the most worrisome hypertension treatment outcomes, followed by myocardial infarction (0.191), acute heart failure (0.176), and common adverse drug reactions (ADRs) (0.091). Among ADR, dyspnea was consistently ranked as the most concerning. Stratified analyses revealed variations in outcome prioritization: patients with prior stroke or acute heart failure strongly prioritized stroke avoidance, whereas those with myocardial infarction or multiple events emphasized avoiding death.ConclusionsThis is the first study to apply AHP to hypertension treatment preferences, identifying stroke and death as equally worrisome outcomes, clearly prioritized for avoidance. Thus, prolonging life is not universally the primary goal among patients. Integrating patient preferences into clinical decision-making may support a more patient-centered approach and improve treatment adherence and outcomes.

Background/Objectives: Pediatric-onset multiple sclerosis (POMS), defined as onset before age 18, is increasingly recognized as a distinct entity, often associated with a more burdensome disease course and earlier disability milestones than adult-onset MS. Although comorbidities may significantly affect disease progression and outcomes, their prevalence, incidence, risk, and characteristics in POMS remain poorly understood. To date, no systematic review has comprehensively evaluated comorbidities in POMS. The primary aim is to systematically identify and synthesize available evidence on the prevalence, incidence, risk, and characteristics of these comorbidities in POMS populations, as well as any reported effects on disease course, treatment outcomes, and overall clinical management. Methods: We will conduct a systematic review and meta-analysis following a hierarchical and pragmatic analytical strategy tailored to the expected heterogeneity and limited evidence base in POMS. MEDLINE (via PubMed) and Embase (produced by Elsevier) will be searched without date restrictions, combining controlled vocabulary terms (MeSH/Emtree) and relevant keywords for POMS and 15 predefined comorbidity categories. Study selection, abstract and full-text screening, and data extraction will be performed independently by two reviewers using predefined criteria and standardized forms. The primary quantitative outcome will be the pooled prevalence of comorbidities. Where study design and reporting permit, incidence rates will be assessed as secondary outcomes, and risk estimates (e.g., odds ratios) will be evaluated only in studies with appropriate comparator groups. Meta-analyses will be conducted using random-effects models when pooling is feasible. Heterogeneity will be assessed using the I2 statistic and Cochran’s Q test, with sensitivity and subgroup analyses performed only when sufficient data are available. When quantitative synthesis is not appropriate due to limited data or substantial heterogeneity, findings will be summarized descriptively. Publication bias will be evaluated using funnel plots and, where applicable, Egger’s and Begg’s tests. This protocol adheres to PRISMA and PRISMA-P guidelines. Discussion: A systematic quantification of comorbidity prevalence, incidence (where available), and risk, together with POMS-specific characteristics and any reported impact on clinical outcomes, is anticipated to provide a crucial evidence base for guiding screening, refining management strategies, and informing future research directions. Ultimately, these findings may improve clinical outcomes and quality of life for children and adolescents with MS.

Early pregnancy loss (EPL) is associated with significant emotional burden. While multiple management options exist, psychological aspects are often underrepresented in decision-making support. The objective of this study is to identify criteria that are important to women when choosing between expectant, medical, and surgical management of EPL, with particular attention to psychological aspects. A mixed-methods study using the Analytic Hierarchy Process (AHP) was conducted. Criteria were identified via literature review and a focus group. Thirty-seven women with EPL history completed structured telephone interviews with pairwise comparisons. Quantitative data were analyzed to calculate criterion weights and assess consistency. Logistic regression explored factors associated with inconsistent responses. Among 37 participants, ‘Minimizing psychological distress’ emerged as the most important criterion (local weight = 0.381), with sub-criteria such as ‘Experiencing miscarriage as a natural process’ (0.384; 0.252) and ‘Avoiding hospital treatment’ (0.355; 0.425) ranked most important for women preferring expectant and medical management, respectively. Women preferring surgical management prioritized ‘Short time to miscarriage completion’ (0.389). Sixty-five percent of participants demonstrated acceptable preference consistency (consistency ratio ≤ 0.2). Lower education showed the greatest and statistically significant negative influence on the consistency of the preferences in the regression models. Preferences varied by treatment choice, indicating that psychological distress is defined differently across women. The AHP method enabled nuanced insights into individual decision-making. Emotional factors may influence preference patterns and should be considered in clinical counselling. These findings support the need for individualized counselling and shared decision-making. The results may inform the development of clinical tools and guidelines.

BACKGROUND:Cost-effectiveness of family conferences on deprescribing with joint prioritization of treatment goals in primary care has not been investigated so far. We assessed cost-effectiveness in the cluster-randomized controlled COFRAIL trial conducted with general practitioners and 521 older frail patients with polypharmacy cared for at home in Germany. METHODS:Hospital admissions averted and quality-adjusted life years (QALYs) gained were associated with costs from the German Social Insurance perspective. We applied adjusted GLM regressions with specified distributions to estimate group differences on imputed data, plotted bootstrap cost-outcome pairs by simulated resampling of the study population to illustrate uncertainty and calculate the probability of cost-effectiveness given a willingness-to-pay threshold, and assessed robustness in sensitivity analyses. RESULTS:Intervention-related costs were €391 (US$459) per capita. On 100 people, the COFRAIL intervention had about 7 more hospital admissions (95% CI: -12; 26), 2 QALYs gained (95% CI: -1; 6), and additional costs of €117,681 (95% CI: -28,838; 264,201)/US$138,027 (95% CI: -33,824; 309,880) or €124,866 (95% CI: -12,649; 262,380)/US$146,455 (95% CI: -14,836; 307,745) without or with hospital costs, respectively, compared to usual care. By bootstrapping, we observed the COFRAIL intervention to have higher costs and more hospital admissions with a relative frequency of 28%-78%, or in terms of QALYs 57%-91%. The COFRAIL intervention had additional costs of €50,966 (US$59.778) per QALY gained with a 46% probability of being cost-effective at a willingness to pay of €45,000/QALY (≈US$50,000/QALY). CONCLUSION:The COFRAIL intervention affected QALYs rather than hospital admissions after 12 months. The intervention tended to be associated with higher costs and QALYs but was less likely to be cost-effective than usual care at commonly used willingness-to-pay thresholds. Long-term cost-effectiveness should be assessed.

In Germany, all new drugs undergo an early benefit assessment (EBA) by the decision-making body (G-BA). Due to limited access to clinical data in pediatric healthcare since 2017, evidence transfer has allowed for data from adult studies to be used in the EBA of pediatric drugs. This study examines the acceptance of evidence transfer, aiming to understand its correlation with granted added benefit. By searching the G-BA database, relevant EBAs were identified. In addition to descriptive statistics, agreement statistics regarding binary and ordinal extent of added benefit and binary logistic regression with and without intercept were performed to investigate acceptance of evidence transfer, juxtaposing it with manufacturers’ claims, and to evaluate the impact of identified factors on evidence transfer. In 14 of 36 identified EBAs, the evidence transfer was accepted by the G-BA. They referred to four therapeutic areas, received a non-quantifiable added benefit and were subject to a pediatric investigation program. Non-quantifiable added benefit implies an added value in itself which can range from minor to major added benefit and is considering the genuine uncertainty mainly induced in theese EBAs due to evidence transfer, which is not allowing a quantification of an added benefit. The binary agreement between manufacturers’ claims and G-BA’s appraisals was less than by chance [kappa − 0.054 (− 0.158 to 0.050)] whereas the ordinal agreement became fair [kappa 0.333 (0.261–0.406)]. Congruence of the mechanism of action, alignment of disease pattern, transferability of efficacy and safety, and same comparator were fundamental for evidence transfer. Additionally, supportive evidence, therapeutic breakthroughs, and small-scale approval enhanced the acceptance of evidence transfer. The regression models yielded similar results showing different model fit and explained variance. Evidence transfer hinges upon fulfilling various minimum criteria and additional supportive evidence. Availability of study data from adult or older patients and the pediatric group under evaluation is crucial.

BackgroundRandomized controlled trials are the standard for health technology assessment, but when they are infeasible or unethical, single-arm trials (SATs) are submitted.ObjectivesThis study examined when SATs were accepted for added benefit by the Institute for Quality and Efficiency in Health Care (IQWiG) and/or the Federal Joint Committee (G-BA) in Germany.MethodsWe identified health technology assessments via the AMNOG-Monitor database through December 2024, with additional details from G-BA documents. We compared the SATs and other evidence for added benefit decisions (granted/not granted), stratified by orphan drug status, special marketing authorization, approved indication (chronic hepatitis C/others), and population (adults/children). Added benefit claims by manufacturers, IQWiG recommendations, and G-BA appraisals were compared.ResultsAmong 1738 G-BA decisions, 85.8% (1491/1738) of the subpopulations were fully assessed by IQWiG, with 13.5% (202/1491) based on SATs. Among the 247 orphan drugs assessed by the G-BA, 37.7% (93/247) were SAT-based. Overall, SAT-based assessments demonstrated an added benefit in 12.2% (36/295) of cases. This included 13.4% (27/202) of full assessments and 9.7% (9/93) of orphan drug assessments. IQWiG accepted only 18.5% (5/27) of the SATs endorsed by the G-BA. Statistical tests revealed significant differences between manufacturers' claims, IQWiG recommendations, and G-BA appraisals. SATs were most frequently accepted for chronic hepatitis C treatments (mostly with non-standard marketing authorization) and paediatric indications. The G-BA cited reasons such as dramatic effects, rare diseases, a lack of alternatives, or fewer side effects, although justifications were often unclear.ConclusionAcceptance rates for SATs remain low, and criteria for added benefit are not always explicitly defined. To enable benefit assessments when randomised controlled trials are infeasible or unethical, clear and binding criteria developed in collaboration with the G-BA are essential.

INTRODUCTION:To examine the long-term health and economic impact of a lifestyle diabetes prevention program in people with high risk of developing type 2 diabetes in Germany. RESEARCH DESIGN AND METHODS:We assessed the lifetime cost-effectiveness of a 2-year pragmatic lifestyle program for preventing type 2 diabetes targeting German adults aged 35-54 and 55-74 years old with hemoglobin A1c (HbA1c) from 6.0% to 6.4%. We used the Centers for Disease Control and Prevention RTI Diabetes Cost-Effectiveness Model to run a simulation on the program effectiveness. We estimated incremental health benefits in quality-adjusted life years (QALYs) and costs using an established simulation model adapted to the German context, from a healthcare system and societal perspective. The cost-effectiveness of the program was measured by incremental cost-effectiveness ratios (ICERs) in cost per QALY. We projected the number of type 2 diabetes cases prevented by participation rate if the program was implemented nationwide. RESULTS:The lifestyle program would result to more QALYs and higher costs. The lifetime ICERs were 14 690€ (35-54 years old) and 14 372€ (55-74 years old) from a healthcare system perspective and cost saving (ICER=-3805€) and cost-effective (ICER=4579€), respectively, from a societal perspective. A total of 10 527 diabetes cases would be prevented over lifetime if the program was offered to all eligible people nationwide and 25% of those would participate in the program. CONCLUSIONS:Implementing the lifestyle intervention for people with HbA1c from 6.0% to 6.4% could be a cost-effective at standard willingness to pay level strategy for type 2 diabetes prevention. The intervention in the younger cohort could be cost saving from a societal perspective. The successful implementation of a lifestyle-based diabetes prevention program could be an important component of a successful National Diabetes Strategy in Germany.

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): University Hospital Düsseldorf Cardiovascular disease (CVD) is the most prevalent non-communicable disease and the leading cause of death globally. Evidence suggests that exercise-based interventions in secondary prevention can mitigate adverse health events. Implementing incentive schemes for patients to engage in physical activity (PA) might be a promising approach to improve adherence. The INPHY trial, a complex intervention that is currently being developed at the University Hospital Düsseldorf, aims at improving PA in people with coronary heart disease (CHD) using monetary and social incentives. The UK Medical Research Council (MRC) framework for the development and evaluation of complex interventions recommends pre-trial health economic modelling to inform the design of the trial. A decision-analytic Markov model was developed to evaluate the costs and benefits of exercise-based, incentivized secondary prevention interventions from a health services provider. A cohort of individuals with a history of myocardial infarction was followed in the model from age 65 years through a total of 25 1-year Markov cycles. Primary outcomes included costs, quality-adjusted life-years (QALY) gained and incremental cost-effectiveness ratios (ICERs). Sensitivity and scenario analyses were performed to reflect parameter and model uncertainty. In the base-case, the incremental QALYs gained from the monetary and social incentives, relative to control, were respectively estimated at 0.01 [95% CI 0.00-0.01] and 0.03 [95% CI 0.02-0.05]. In comparison to control, the implementation of the monetary and social incentive interventions increased the costs by 795€ [95% CI 697-884] and 831€ [95% CI 593-1,191], respectively. ICERs were 24,473€ [95% CI 15,871-38,868] and 112,015€ [95% CI 81,140-169,888] per QALY gained for the social and monetary incentive interventions, respectively. At a per-capita gross domestic product threshold (GDP) of 43,000€/QALY for Germany, the probability that the social and monetary incentive intervention would be seen as cost effective was 100% and 0%, respectively. Exercise-based secondary prevention using incentivized reinforcement schemes might offer a cost-effective strategy to reduce the burden of CHD, offering good value for money in preventing a significant non-communicable disease. Translation of these findings into policy and practice alongside rigorous monitoring and evaluation is important. More epidemiological research from Germany is recommended to reduce the remaining model uncertainty surrounding this decision.

High payer deficits resulted in a regulation in 2010, which forced new pharmaceuticals in Germany after market access to undergo an early benefit assessment (EBA) based on patient-relevant outcomes to prove an added benefit compared to existing therapies.1, 2 This process had been described in detail elsewhere.3 In hemato-oncology, the heterogeneity of the clinical pictures resulted in a large number of endpoints. Survival was often considered decisive. Even survival was not biased by subjective interpretation, it was only suitable to a limited extent due to various factors, including (i) increasing clinical trial duration as longer survival times were achieved even in the palliative setting; (ii) emerging therapies increasingly focused on early-stage diseases and survival might not be measurable in cancers with good prognosis; (iii) fatal events were rare when cancer prognosis was good, leading to increasing sample size to demonstrate statistical difference; (iv) wider therapeutic options and additional number of treatment lines increased the complexity to isolate the effect of the drug, intensified even more due to bias linked to crossover effects; (v) in settings with long postprogression survival due to effective posttrial therapy or crossover, progression could be used as the primary endpoint.4-7 This was reflected in the approach of the European Medicines Agency, which had chosen a decisive endpoint other than survival in more than half of the newly approved hemato-oncology drugs since 2009.8 However, the value of treatment response endpoints (TREs) in hemato-oncology has not been systematically investigated within the framework of EBA and compared with everyday clinical practice. All EBAs of hemato-oncological drugs with a resolution of the decision maker (Federal Joint Committee, FJC) were included. Regarding the consideration of the TREs by the FJC, the binomial proportion was determined on an indication-specific basis.9 TREs used by the manufacturers to prove an added benefit were described and their significance in clinical practice was presented. The assessment of TREs relevance in clinical practice was derived from the German Onkopedia Guidelines and Oncology Guidelines Program regarding therapy goals, prognosis, and influence on therapy decisions. The acceptance of TREs by the FJC was contrasted with their relevance in clinical practice using Cohen's Kappa and interpreting the results according to Altmann et al.10 Until end of 2021, there were 72 FJC resolutions for hemato-oncological drugs, of which in 48 cases 64 TREs were used by the manufacturer to demonstrate an added benefit (Table 1). Of these cases, 71% used one, 25% two, and 4% three TREs. Number of EBAs with TREs (accepted) Number of TREs claiming added benefit (accepted) Binomial proportion (95% CI) The FJC only accepted a total of nine TREs as patient relevant in eight EBAs. Of the 55 nonaccepted TREs, 29% were primary endpoints in pivotal trials. In total, there were FJC resolutions in 17 hemato-oncological indications. The eight EBAs with accepted patient-relevant TREs were distributed across the following indications: chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, cutaneous T-cell lymphoma, myelofibrosis, polycythemia vera, and systemic anaplastic large cell lymphoma (Table 1). The overview showed that the TREs accepted by the FJC either (i) in 6/9 TREs a symptom response associated with the endpoint could be shown (EBAs of Brentuximab vedotin for the treatment of relapsed/refractory Hodgkin's lymphoma, relapsed/refractory systemic anaplastic large cell lymphoma, and CD30+ cutaneous T-cell lymphoma, TRE: complete remission; EBA of Fedratinib for the treatment of myelofibrosis and EBAs of Ruxolitinib for the treatment of polycythemia vera and myelofibrosis, TRE: spleen response) or (ii) in 2/9 TREs a treatment that was burdensome for patients and associated with an increased risk of treatment-related side effects could be prevented by reaching a target value (EBA of Ropeginterferon alfa-2b for the treatment of polycythemia vera, TRE: hematological response; EBA of Ruxolitinib for the treatment of polycythemia vera, TRE: hematocrit control) or (iii) in 1/9 TREs the high healthcare relevance of the effects of the therapy justifies the acceptance (EBA of Idelalisib for the first-line treatment of CLL with 17p-deletion/TP53-mutation in combination with Rituximab, TRE: overall response rate). The most common reason for accepting a TRE was that a symptom response associated with the endpoint could be shown. Out of 55 not-accepted TREs, the rejection as a patient-relevant endpoint was clearly justified by the FJC in the supporting reasons in 23 cases. It turned out that the reasons for rejection were distributed very differently in the individual indications. In acute lymphatic leukemia (ALL) and acute myeloid leukemia (AML), clear reasons were given for almost all TREs as to why they were not recognized as patient relevant in the EBA. In indications such as CLL and multiple myeloma, the rejection was only clearly justified for a few TREs by the FJC. A comparison with the TREs accepted as patient relevant by the FJC showed that the endpoint “complete remission” was accepted as patient relevant in three EBAs, whereas in 16 cases, it was not accepted. The cases differed in the operationalization of the endpoint. All nonaccepted TREs were not symptom-related but were recorded exclusively on the basis of laboratory tests or imaging procedures such as PET. The second main reason for rejection was that the TRE was not validated as a surrogate parameter for other patient-relevant endpoints. The hurdles in surrogate validation as part of the EBA have already been discussed elsewhere.11 The binomial proportion of TREs being accepted depends on indication (Table 1). In 10 of 16 indications, no TRE was accepted by the FJC. Within the indications with accepted TREs the proportion of acceptance ranged between 8.3% in CLL and 100.0% in myelofibrosis. Overall indications, the binomial proportion was 0.14 (95% confidence intervals (CI) 0.07 to 0.25). With the exception of the indications of ALL, CLL, and multiple myeloma, the 95% CIs included 0.50 due to the relatively small numbers of TREs observed and the strong heterogeneity between the indications (chi-square test = 36.417, df = 15, p = 0.002). Of the 11 cases with agreement, five endpoints were accepted as part of the EBA and, according to the guidelines, were also relevant in clinical practice. Six endpoints were not accepted by the FJC as patient relevant and were not listed in the guidelines (Table 1). Except for two cases, the decisions of the FJC were consistent; that is, a specific TRE was accepted or rejected in one indication regarding all EBAs within this indication. In the indication of systemic anaplastic lymphoma, the FJC accepted the endpoint of complete remission in one case but not in another case. In the EBA of brentuximab vedotin (systemic anaplastic large cell lymphoma; first line; combination with cyclophosphamide, doxorubicin, and prednisone), in which the complete remission was not accepted, there was a significant difference across the entire patient population, but the difference was not statistically significant in patients with B symptoms at baseline.12 Of the 18 TREs with disagreement on the value in the EBA compared to the clinical practice, 17 were recognized by the FJC as not being patient-relevant. In contrast, these endpoints were listed in the guidelines as therapeutic goals or were relevant for prognosis or the treatment decision. Only reduction of spleen volume by ≥35% in polycythemia vera was accepted by the FJC, which was not listed as a relevant endpoint in the guideline. Summing up the TREs in the various indications, 47 of 64 TREs were not accepted in the respective EBAs, which according to the guideline were important in clinical practice. With a Cohen's Kappa = 0.01 (standard error = 0.04, 95% CI −0.07 to 0.08), there was only a poor agreement between accepted TREs in EBA and their value in clinical practice. In addition, the respective odds ratio of TREs acceptance in clinical guidelines compared to EBAs indicated with 1.17 (95% CI 0.13 to 10.79) statistical independence between both. It became apparent that the EBA in Germany and their preceding market authorization as well as the guidelines often came to different conclusions on the value of endpoints, although they were usually based on identical clinical evidence. This was also discussed by relevant medical societies and also applied at the European level.13, 14 TREs had a relevant meaning in clinical practice in many therapeutic areas and especially in hemato-oncology as overall survival oftentimes could not be captured in regular study duration. For example, the median survival time for multiple myeloma had more than tripled over the last 20 years to almost 70 months.15 Minimal residual disease was an important prognostic factor in the treatment of ALL, CLL, and multiple myeloma. Achieving a complete remission was often the primary therapy goal in the treatment of ALL, AML, or diffuse large B-cell lymphoma, because this moved patients usually on to follow-up care and there was no need for any further burdensome treatment associated with side effects. In CLL, a change in therapy was necessary if no complete or partial remission was achieved after first-line therapy. In Hodgkin's lymphoma and mantle cell lymphoma, allogeneic transplantation, a potentially curative treatment, was an option for relapsed patients if they had achieved (partial) remission. The question arises whether patient-relevance was defined too narrowly in hemato-oncology in the context of EBA ignoring the value of TREs in clinical practice. It is therefore crucial that the chosen endpoints are meaningful to clinicians, patients, and policymakers that are the end-users of evidence generated by these trials. Open access funding enabled and organized by Projekt DEAL.

Health-related quality of life (HRQoL) is an important outcome within early benefit assessment (EBA) of new oncological medicines in German HTA. The study examines the extent to which results on HRQoL presented are based on robust evidence. The study is based on the completed oncological EBAs, whose start date is latest January 2016 (N = 59). Documents of the EBAs with the 6 most common HRQoL elicitation instruments in oncology patients (EORTC QLQ-C30, EQ-5D, FACT-P, FACT-M, EORTC QLQ-MY20, FACT-Lym) were reviewed in full text and information on age, gender, degree of disease severity was collected via content categorization. Furthermore, ethnicity and geographic region in treatment and validation studies, and psychometric quality criteria in validation studies (validity, reliability, responsiveness) were documented as well. HRQoL is elicited in 47/59 EBAs and reported to derive additional benefit. In particular, 54% of the validation studies fully matched and 18% proportionately matched the indication of the drug being evaluated. Statistically significant group differences were found in 83% for age, 54% for gender, 83% for disease severity, 59% for ethnicity and 71% for the geographical region. Regarding the validation studies, in 2 cases, subscales or components of the elicitation instruments were not considered, in 2 further cases they were only partly considered and in 4 cases they showed for subscales or components of the elicitation instruments unequal robustness. Sufficient evidence for the validity of HRQoL instruments requires the implementation of appropriate validation studies based on the treatment interventions of pivotal studies. The focus should be on disclosing evidence gaps and discussing restrictions in the course of the claimed validity. In the future, efforts should be intensified to close such gaps through new validation studies.

Single-arm trials (SAT) using external comparator (EC) data are increasingly submitted for Health Technology Assessment (HTA). We compared the submission rate, acceptance rate and success factors for real world data (RWD) compared to other evidence as ECs. Furthermore, we evaluated whether the assessment was positive.

Objective Increased healthcare utilization and costs have been reported in individuals with diabetes with comorbid depression. Knowledge regarding cost differences between individuals with diabetes alone and those with diabetes and diagnosed/undiagnosed depression is however scarce. We therefore compared utilization and costs for patients with diabetes and no depression and patients with diabetes and documented depression diagnosis or self-reported depression symptoms for several cost components, including mental healthcare costs. Research Design and Methods Data from a 2013 cross-sectional survey of randomly sampled members of a nationwide German statutory health insurance (SHI) provider with diabetes (n=1,634) were linked individually with SHI data covering four quarters before and after the survey. Self-reported depression symptoms were assessed using the PHQ-9, with depression diagnosis taken from SHI data. We analyzed healthcare utilization and costs, using regression analysis to calculate cost ratios adjusted for sociodemographic/socioeconomic factors and comorbidities for two groups: A) no symptoms, no diagnosis; B) symptoms or diagnosis. Our explorative sub-analysis analyzed subgroups with either symptoms or diagnosis separately. Results Annual mean total healthcare costs were higher for patients with comorbid depression (€5,629 (95% CI: €4,987-€6,407)) than without (€3,252 (95% CI: €2,976-€3,675), the cost ratio being 1.25 (1.14-1.36)). Regression analysis showed that excess costs were highly associated with comorbidities. Mental healthcare costs were very low for patients without depression (€2/€4) and still relatively low for those with depression (€111/€76). Conclusions Costs were significantly higher when comorbid depression was present, either as symptoms or diagnosed. Excess costs for mental-health services were rather low.