Twelve years of European cancer drug approval-a systematic investigation of the 'magnitude of clinical benefit'.

BACKGROUND: The magnitude of clinical benefit of solid cancer drugs can be standardly assessed via the Magnitude of Clinical Benefit Scale (MCBS) developed by the European Society for Medical Oncology (ESMO). We applied two ESMO-MCBS versions to the last 12 years of European cancer drug approval and compared two predefined marketing authorisation timeframes to identify potential score changes over time. MATERIAL AND METHODS: Originator solid cancer drugs and indication extensions that were approved between 1 January 2009 and 31 October 2020 by the European Medicines Agency (EMA) were included in our analyses. To evaluate the clinical benefit of these cancer indications, the original ESMO-MCBS (v 1.1) and a locally adapted ESMO-MCBS version were applied to the study sample. Thus, two ESMO-MCBS versions were compared, and an additional analysis was conducted to identify potential score differences between two approval timeframes 2009-2014 versus 2015-2020. RESULTS: A total of 144 cancer indications intended as curative (n = 9) or non-curative (n = 135) treatment options were eligible for an ESMO-MCBS assessment. Solely a minority of the assessed cancer indications met the meaningful clinical benefit (MCB) criteria independent of the applied version of the scale and treatment intention (original: n = 48/144, 33.3% versus adapted: n = 27/144, 18.8%). Comparing the two EMA approval timeframes, a growing number of approved cancer indications could be observed: 2009-2014: n = 9/year versus 2015-2020: n = 14/year. In addition, almost no difference in the proportion of cancer indications that have met the MCB criteria was detectable when comparing the predefined authorisation timeframes (MCB increase original: +4.1% and adapted: +3.9%). CONCLUSION: Applying both versions of the ESMO-MCBS can help to identify potentially beneficial cancer indications, but also those with rather uncertain or low clinical benefit and thus, support the fair allocation of limited health care resources.

Monitoring evidence on overall survival benefits of anticancer drugs approved by the European Medicines Agency between 2009 and 2015.

OBJECTIVE: The introduction provisional approval strategies increases the approval of anticancer drugs with ambiguous benefit-risk profiles. Thus, in many instances, there is lacking evidence about overall survival (OS) at the time of marketing authorisation. Our objective was to monitor and characterise therapies with ambiguous benefit-risk profiles and identify any postapproval updates on median OS after at least 3 years of approval by the European Medicines Agency (EMA). METHODS: We included all originator anticancer drugs with initially ambiguous benefit-risk profiles that received marketing authorisation by the EMA between January 1, 2009 and May 31, 2015. Our monitoring timeframe was at least 3 years after EMA approval. To identify study updates, the following three sources were included: clinicaltrials.gov, European Public Assessments Reports and PubMed. RESULTS: In total, we identified 102 eligible approval studies. Out of these, a negative difference in median OS or no information was available in 43 (42.2%) instances. During monitoring, 14 updates with accessible positive information on OS could be identified. Including monitoring results, there are still 29 remaining therapies (28.4%) where no or negative information (n = 24 [23.5%] and n = 5 [4.9%], respectively) regarding OS is present at least 3 years after EMA approval. CONCLUSION: One-third of oncology drugs with ambiguous benefit-risk profiles at the time of approval fail to demonstrate a survival benefit even after several years of marketing authorisation. Systematic and transparent postapproval monitoring mechanisms will be of high relevance to assure a clinically relevant patient benefit, since the trend towards faster access to medicines with uncertain benefit is increasing rather than declining.

Exercise during pregnancy and its impact on mothers and offspring in humans and mice.

Exercise during pregnancy has beneficial effects on maternal and offspring's health in humans and mice. The underlying mechanisms remain unclear. This comparative study aimed to determine the long-term effects of an exercise program on metabolism, weight gain, body composition and changes in hormones [insulin, leptin, brain-derived neurotrophic factor (BDNF)]. Pregnant women (n=34) and mouse dams (n=44) were subjected to an exercise program compared with matched controls (period I). Follow-up in the offspring was performed over 6 months in humans, corresponding to postnatal day (P) 21 in mice (period II). Half of the mouse offspring was challenged with a high-fat diet (HFD) for 6 weeks between P70 and P112 (period III). In period I, exercise during pregnancy led to 6% lower fat content, 40% lower leptin levels and an increase of 50% BDNF levels in humans compared with controls, which was not observed in mice. After period II in humans and mice, offspring body weight did not differ from that of the controls. Further differences were observed in period III. Offspring of exercising mouse dams had significantly lower fat mass and leptin levels compared with controls. In addition, at P112, BDNF levels in offspring were significantly higher from exercising mothers while this effect was completely blunted by HFD feeding. In this study, we found comparable effects on maternal and offspring's weight gain in humans and mice but different effects in insulin, leptin and BDNF. The long-term potential protective effects of exercise on biomarkers should be examined in human studies.

Five years of EMA-approved systemic cancer therapies for solid tumours-a comparison of two thresholds for meaningful clinical benefit.

OBJECTIVE: Several societies have proposed frameworks to evaluate the benefit of oncology drugs; one prominent tool is the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS). Our objectives were to investigate the extent of European Medicines Agency (EMA)-approved cancer drugs that meet the threshold for 'meaningful clinical benefit' (MCB), defined by the framework, and determine the change in the distribution of grades when an adapted version that addresses the scale's limitations is applied. METHODS: We identified cancer drugs approved by the EMA (2011-2016). We previously proposed adaptations to the ESMO-MCBS addressing its main limitations, including the use of the lower limit of the 95% confidence interval in assessing the hazard ratio. To assess the MCB, both the original and adapted ESMO-MCBS were applied to the respective approval studies. RESULTS: In total, we identified 70 approval studies for 38 solid cancer drugs. 21% of therapies met the MCB threshold by the original ESMO-MCBS criteria. In contrast, only 11% of therapies met the threshold for MCB when the adapted ESMO-MCBS was applied. Thus 89% and 79% of therapies did not meet the MCB threshold in the adapted and original ESMO-MCBS, respectively. CONCLUSIONS: In most of the cancer drugs, the MCB threshold is not met at the time of approval when measured using both ESMO-MCBS scales. Since approval status does not translate into a MCB, stakeholders and decision makers should focus on the benefit/risk ratio of anticancer drugs to assure an appropriate allocation of resources in health care systems.

["I would not even think of applying!" - Barriers to Claiming Benefits for Rehabilitation Services for Children and Adolescents from Families' Perspectives]. / "Das würde ich gar nicht erst beantragen!" ­ Barrieren der Inanspruchnahme einer Kinder- und Jugend-Rehabilitations-Maßnahme aus Sicht der Familien.

Background Medical rehabilitation is recognized as an effective health care service to promote and protect health and social participation of children and adolescents. Although the number of children and adolescents with chronic conditions is growing, applications for rehabilitation have declined substantially since 2008. The aim of the study is to identify barriers that prevent families from claiming benefits for rehabilitation services and to give recommendations for actions. Methods In this explorative study, guided qualitative interviews with families with children and adolescents eligible for benefits were conducted. The analysis of the transcribed interviews followed the iterative process of content analysis (deductive and inductive development of main and sub-categories). Results 14 families (with 16 index-children) participated in the study. The results showed high levels of psychosocial burden of families and yet barriers to access services on a structural, disease-specific, and individual level. We identified three main topics in which families recommended modifications: (a) information policy, (b) family centeredness perspectives and flexibility, and (c) cross-sectoral collaboration/health care management. Conclusions Results indicate that families perceive the current pediatric rehabilitation services to lack fitting and flexibility. In general, a new approach of information and counselling, a more family centered perspective and integration of rehabilitation services in a comprehensive and coordinated health care structure are needed.

Anemia in patients with Wegener's granulomatosis.

AIMS: Anemia is commonly observed among patients with chronic kidney disease (CKD). No such information is available for patients with a history of systemic vasculitis. METHODS: We examined the prevalence of anemia, the response to therapy with erythropoiesis-stimulating agents (ESA), and the association of anemia with the kidney function in clinically stable patients with Wegener's granulomatosis in a retrospective, single-center study. RESULTS: The mean hemoglobin concentration of 36 patients (mean age: 58 years; 15 female, 21 male; mean duration of disease: 4.6 years) was 13.0+/-2.1 g/dl, and the mean estimated glomerular filtration rate (eGFR) was 41+/-21 ml/min/1.73 m(2). 14 of 36 patients (38.8%) presented with anemia (hemoglobin concentration < 12 g/dl in women, < 13 g/dl in men, or ESA therapy). In patients with a CKD Stage 3 or 4, anemia was present about twice as much as compared to the Third National Health and Nutrition Examination Survey (NHANES III) population. The hemoglobin concentration, however, was not associated with a change of kidney function (p = 0.1578). CONCLUSIONS: We found a higher prevalence of anemia in patients with Wegener's granulomatosis, as compared to the NHANES III population. The hemoglobin concentrations showed no association with changes of kidney function.