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Background and Objectives: Drawing causal conclusions from real-world data (RWD) poses methodological challenges and risk of bias. We aimed to systematically assess the type and impact of potential biases that may occur when analyzing RWD using the case of progressive ovarian cancer. Methods: We retrospectively compared overall survival with and without second-line chemotherapy (LOT2) using electronic medical records. Potential biases were determined using directed acyclic graphs. We followed a stepwise analytic approach ranging from crude analysis and multivariable-adjusted Cox model up to a full causal analysis using a marginal structural Cox model with replicates emulating a reference randomized controlled trial (RCT). To assess biases, we compared effect estimates (hazard ratios [HRs]) of each approach to the HR of the reference trial. Results: The reference trial showed an HR for second line vs. delayed therapy of 1.01 (95% confidence interval [95% CI]: 0.82e1.25). The corresponding HRs from the RWD analysis ranged from 0.51 for simple baseline adjustments to 1.41 (95% CI: 1.22e1.64) accounting for immortal time bias with time-varying covariates. Causal trial emulation yielded an HR of 1.12 (95% CI: 0.96e1.28). Conclusion: Our study, using ovarian cancer as an example, shows the importance of a thorough causal design and analysis if one is expecting RWD to emulate clinical trial results.

Evidence on long-term effectiveness and cost effectiveness of treatment sequences for multiple myeloma (MM) is sparse. We used published data and country-specific data to assess the cost effectiveness of four-line treatment sequences for elderly transplant-ineligible patients with MM in Serbia.We developed a Markov cohort model to compare long-term effectiveness and cost effectiveness of five sequential MM treatment alternatives from the perspective of the national healthcare provider. Effectiveness parameters on progression, mortality and adverse events were extracted from published clinical trials. Costs were based on price lists of the National Health Insurance Fund. We compared life expectancy, costs, and incremental cost-effectiveness ratios among alternative courses of action. The model was analyzed over a lifelong time horizon applying a 3% annual discount rate for effectiveness outcomes and costs. Robustness of the model was tested in multiple deterministic sensitivity analyses.The sequences were defined by the frontline treatment: MPT (melphalan-prednisone-thalidomide), MPV (melphalanprednisone-bortezomib), CTD (cyclophosphamide-thalidomide-dexamethasone), VCD (bortezomib-cyclophosphamidedexamethasone) and BP (bendamustine-prednisone). MPV sequence resulted in the highest remaining life expectancy (4.76 life years). Cost-effectiveness analysis resulted in three non-dominated strategies: MPT, VCD, and MPV sequences, with an incremental cost-effectiveness ratio of EUR 35,300 per life-year gained (LYG) for VCD and EUR 47,200/LYG for MPV relative to MPT.MPV sequence was the most effective in terms of life expectancy for elderly transplant-ineligible MM patients in Serbia. Bortezomib-based strategies would be recommended for the frontline treatment of patients with MM in Serbia if the willingness-to-pay threshold is around EUR 35,000-60,000/LYG.O dolgoročni uspešnosti in stroškovni učinkovitosti zaporedij zdravljenja multiplega mieloma (MM) ni veliko dokazov. Na podlagi objavljenih podatkov in podatkov za posamezne države smo ocenili stroškovno učinkovitost štirih zaporedij zdravljenja starejših bolnikov z MM, ki niso primerni za presaditev, v Srbiji.Za primerjanje dolgoročne uspešnosti in stroškovne učinkovitosti petih alternativ zaporednega zdravljenja MM z vidika nacionalnega izvajalca zdravstvenega varstva smo razvili kohortni model Markova. Parametre uspešnosti glede napredovanja, umrljivosti in neželenih dogodkov smo pridobili iz objavljenih kliničnih preskušanj. Stroški temeljijo na cenikih nacionalnega sklada za zdravstveno zavarovanje. Med različnimi ukrepi smo primerjali pričakovano življenjsko dobo, stroške in mejno razmerje stroškovne učinkovitosti. Model smo analizirali v vseživljenjskem časovnem okviru, pri čemer smo za rezultate uspešnosti in stroške uporabili 3-odstotno letno diskontno stopnjo. Robustnost modela smo preizkusili z več determinističnimi analizami občutljivosti.Zaporedja so bila opredeljena z zdravljenjem v prvi liniji: MPT (melfalan-prednizon-talidomid), MPV (melfalanprednizon-bortezomib), CTD (ciklofosfamid-talidomid-deksametazon), VCD (bortezomib-ciklofosfamid-deksametazon) in BP (bendamustin-prednizon). Pri zaporedju MPV je bila pričakovana preostala življenjska doba najdaljša (4,76 leta življenja). Pri analizi stroškovne učinkovitosti so bile ugotovljene tri neprevladujoče strategije: zaporedja MPT, VCD in MPV z mejnim razmerjem stroškovne učinkovitosti 35.300 EUR na pridobljeno leto življenja (LYG) za VCD in 47.200 EUR/LYG za MPV glede na MPT.Zaporedje MPV je bilo najuspešnejše v smislu pričakovane življenjske dobe starejših bolnikov z MM, ki niso primerni za presaditev, v Srbiji. Strategije, ki temeljijo na bortezomibu, bi bile priporočljive za zdravljenje bolnikov z MM v prvi liniji v Srbiji, če je prag pripravljenosti na plačilo približno 35.000–60.000 EUR/LYG.

Key Points Systematically developed set of core PROs in MDS, involving patients and hematologists in a 2-round Delphi survey.Core PROs will support unified outcome measurement and facilitate inclusion of reliable patient information in MDS disease care., Visual Abstract, Patient-reported outcomes (PROs) are relevant and valuable end points in the care of patients with myelodysplastic syndromes (MDS). However, a consensus-based selection of PROs for MDS, derived by both patients and hematologists, is lacking. We aimed to develop a core set of PROs for patients with MDS as part of the prospective European LeukemiaNet MDS (EUMDS) Registry. According to international guidelines, candidate PROs were identified from a comprehensive literature search of MDS studies. Overall, 40 PROs were selected and evaluated in a two-round Delphi survey by 40 patients with MDS and 38 hematologists in the first round and 38 patients and 32 hematologists in the second round. Based on an agreement scale and predefined inclusion criteria, both patients and hematologists selected “general quality of life” as a core PRO. Hematologists also selected “transfusion-dependency burden” and “ability to work/activities of daily living” as core PROs. The second Delphi round increased PRO rating agreements. Statistically significant rating differences between patients and hematologists were observed for 28 PROs (Mann-Whitney U test; P < .05) in the first round and for 19 PROs in the second round, with “disease knowledge” and “confidence in health care services” rated notably higher by patients. The overall mean PRO ratings correlation between the 2 groups was moderate (Spearman’s rank correlation coefficient = 0.5; P < .05). This first consensus on a core set of PROs jointly developed by patients and hematologists forms the basis for patient-centered care in daily practice and clinical research.

FH is still underdiagnosed. Cost-effectiveness results of preventive screening strategies vary. We aimed at systematically assessing the benefits, harms and cost effectiveness of screening for familial hypercholesterolemia (FH) and at providing an overview of the main characteristics and methodological approaches of applied decision-analytic models.A systematic literature search was conducted in MEDLINE, EconLit, CRD-databases and the CEA-registry for FH screening starting 2012. Earlier studies were included from a published systematic review. Results were reported in standardized semi-quantitative evidence tables. Costs were converted to current euros. Incremental cost-effectiveness ratios (ICERs) were recalculated according to economic guidelines.Out of our 211 retrieved studies, eight were included in the review in addition to six studies from an earlier review. Studies were conducted in Europe (UK, The Netherlands, Spain, Poland), USA and Australia evaluating cascade (CS), opportunistic (OS), universal screening (UniS), or combinations using genetic testing, clinical criteria or combinations. Studies evaluating only CS identified strategies with an ICER of up to 37,100 EUR/quality-adjusted life-year (QALY) but some strategies were dominated depending on test combinations. UniS of newborns in combination with CS had an ICER≤15,000 EUR/QALY for sequential cholesterol-genetic screening. In other studies, UniS was dominated by OS/CS.Our systematic review demonstrates the values of FH screening and provides an overview of potentially relevant screening strategies to be tested using a decision-analytic model for the respective country or region. Future research is needed on the transferability of results to other countries and modeling spillover effects to newborns.

(1) Background: The Austrian supply of COVID-19 vaccine is limited for now. We aim to provide evidence-based guidance to the authorities in order to minimize COVID-19-related hospitalizations and deaths in Austria. (2) Methods: We used a dynamic agent-based population model to compare different vaccination strategies targeted to the elderly (65 ≥ years), middle aged (45–64 years), younger (15–44 years), vulnerable (risk of severe disease due to comorbidities), and healthcare workers (HCW). First, outcomes were optimized for an initially available vaccine batch for 200,000 individuals. Second, stepwise optimization was performed deriving a prioritization sequence for 2.45 million individuals, maximizing the reduction in total hospitalizations and deaths compared to no vaccination. We considered sterilizing and non-sterilizing immunity, assuming a 70% effectiveness. (3) Results: Maximum reduction of hospitalizations and deaths was achieved by starting vaccination with the elderly and vulnerable followed by middle-aged, HCW, and younger individuals. Optimizations for vaccinating 2.45 million individuals yielded the same prioritization and avoided approximately one third of deaths and hospitalizations. Starting vaccination with HCW leads to slightly smaller reductions but maximizes occupational safety. (4) Conclusion: To minimize COVID-19-related hospitalizations and deaths, our study shows that elderly and vulnerable persons should be prioritized for vaccination until further vaccines are available.

Background: Although substantial progress has been made in recent decades in eliminating iodine deficiency, iodine deficiency disorders (IDDs) are still prevalent in European countries. Challenges ...

Background: Prevention and treatment of iodine deficiency-related diseases remain an important public health challenge. Iodine deficiency can have severe health consequences, such as cretinism, goi...

Contains fulltext : 229395.pdf (Publisher’s version ) (Open Access) Treatment options for myelodysplastic syndromes (MDS) vary widely, depending on the natural disease course and patient-related factors. Comparison of treatment effectiveness is challenging as different endpoints have been included in clinical trials and outcome reporting. Our goal was to develop the first MDS core outcome set (MDS-COS) defining a minimum set of outcomes that should be reported in future clinical studies. We performed a comprehensive systematic literature review among MDS studies to extract patient- and/or clinically relevant outcomes. Clinical experts from the European LeukemiaNet MDS (EUMDS) identified 26 potential MDS core outcomes and participated in a three-round Delphi survey. After the first survey (56 experts), 15 outcomes met the inclusion criteria and one additional outcome was included. The second round (38 experts) resulted in six included outcomes. In the third round, a final check on plausibility and practicality of the six included outcomes and their definitions was performed. The final MDS-COS includes: health-related quality of life, treatment-related mortality, overall survival, performance status, safety, and haematological improvement. This newly developed MDS-COS represents the first minimum set of outcomes aiming to enhance comparability across future MDS studies and facilitate a better understanding of treatment effectiveness.

Objectives This study aims to describe the use of patient‐reported outcome measures (PROMs) in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) studies and the PROMs landscape. Methods A comprehensive literature review was performed in Medline/Embase (since 2000) and ClinicalTrials.gov (since 2013) to identify PROMs used in MDS and AML clinical studies. Additionally, PROMs included in approved drug labels since 2000 were reviewed. Results Overall, 112 different PROMs were used in 168 published MDS studies and 152 PROMs were used in 172 AML studies. From ClinicalTrials.gov, 16 different PROMs were used in 22 ongoing registered studies in MDS, and 24 were reported in 41 AML studies. The most frequently used PROMs were cancer‐specific (eg, EORTC QLQ‐C30, FACT‐An) or generic (SF‐36, EQ‐5D) instruments, whereas MDS‐ and AML‐specific instruments (eg, QUALMS and QOL‐E in MDS; FACT‐Leu and EORTC QLQ‐Leu in AML) were used in a minority of studies. Two EMA‐approved drugs for MDS included PROMs in their label. EORTC QLQ‐C30 is by far the most frequently used cancer‐specific PROM in both MDS and AML studies. Conclusions This research indicated an underuse of AML/MDS‐specific PROMs for these two indications in clinical studies and labeling claims. However, AML/MDS‐specific instruments in development might be considered in future studies.

Background: Patient-reported outcomes (PROs) play a crucial role in providing patient-centered health care. Inclusion of patients' symptoms, disease perception and quality of life (QoL) provides valuable input for the individual treatment guidance and response evaluation of patients with myelodysplastic syndromes (MDS). Aims: (1) To provide an overview of QoL measurement instruments (QoL-MI) as a multidimensional source of PROs for patients with MDS. (2) To identify core PROs for MDS from the perspective of patients and physicians and to compare the two groups. Methods: (1) To identify studies applying QoL-MI in MDS, we performed a comprehensive systematic literature search (PubMed, Cochrane Library, Scopus, Web of Science). We excluded studies measuring solely one health domain or studies without an English version of the QoL-MI. Studies were screened by two independent reviewers and the observed QoL-MI were summarized in an evidence table. The domains and items within each of the observed QoL-MI were extracted and categorized into potential PROs by six experienced researchers and clinical experts. (2) The selection process included a two-round Delphi survey among MDS patients from France and physicians from 17 different countries as part of the MDS-RIGHT project. Each outcome was scored for importance, using a scale from 1 to 9. Following recommended criteria, highly important outcomes were defined as those scored 7-9 by at least 70% of participants and scored 1-3 by not more than 15%. Outcomes were excluded if scored 1-3 by at least 70% of the participants and 7-9 by not more than 15%. New outcomes were included in the next round if at least two participants suggested them. In the second round, all outcomes were presented together with the ratings of the first round. We used Spearman's rank correlation coefficient to determine the correlation between mean PRO scored by physicians (2nd round) and patients (1st round). Results: (1) Literature search resulted in 2863 studies; 81 studies were included. Overall, we identified twelve generic, six cancer-specific and two MDS-specific QoL-MI. The most commonly used instruments were EORTC QLQ-C30 (26 studies), FACIT-An (17), SF-36 (16), QoL-E (10), and FACIT-BMT (7). These five instruments composed 68% of the total 112 QoL-MI implementations, whereas the MDS-specific QoL-MIs composed only 10%. Based on the QoL-MI review we categorized 40 potential core PROs, which were used in the two-round Delphi survey. (2) In the physicians' Delphi survey, we obtained 38 responses in the first round and 32 responses in the second round. More than 80% of the survey participants had more than ten years of work experience with MDS patients. Three PROs fulfilled the strict inclusion criteria: transfusion dependence, general QoL and ability to work/activities of daily living. After the first round of the patients' survey, 40 answers were analyzed. Confidence in health care, disease knowledge, weakness, general QoL, relationship with friends/relatives, medication use, fatigue, general health, need to rest and shortness of breath were the ten highest ranked PROs. Based on these interim data, most outcomes did not yet fulfill the inclusion criteria and three additional outcomes were suggested: difficulty concentrating, dental problems and fear of falling. The reported low absolute scoring for speaking difficulties, headache, tremor, loss of independence, urinary incontinence and financial difficulties is remarkable. The Spearman coefficients (ρ) showed statistically significant moderate correlation between mean physician and patient scores (ρ=0.51; p-value= 0.0007). Absolute scores differed: patients assigned more often extreme categories (i.e., 1-3 or 7-9) and overall assigned lower importance than physicians. Conclusion: This systematic review demonstrates that the application of QoL scores in MDS patients and the use of MDS-specific QoL-MI are limited so far. Relative PRO-scoring was similar in physicians and patients, but was in general lower in absolute ranking in patients as compared with physicians. However, distinct PROs namely disease knowledge and confidence in health care were identified, which were scored higher by patients than by physicians. These results may form the basis for patient-centered outcome definition. The second patient survey is ongoing and will provide the basis for definition of core PROs in MDS. Disclosures Stojkov: MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) project: Research Funding; Erasmus Mundus-Western Balkans (ERAWEB) programme: Other: Doctoral scholarship. Conrads-Frank:MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) project: Research Funding. Rochau:MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) project: Research Funding. Arvandi:MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) project: Research Funding. Fenaux:Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Efficace:TEVA: Research Funding; Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AMGEN: Research Funding; Orsenix: Consultancy; Incyte: Consultancy; TEVA: Consultancy; Amgen: Consultancy; Lundbeck: Research Funding. Siebert:MDS-RIGHT (Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time) project: Research Funding. Stauder:Teva: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.