Publications by authors named "Joerg Hasford"

102 Publications

Supplementation with subspecies EVC001 for mitigation of type 1 diabetes autoimmunity: the GPPAD-SINT1A randomised controlled trial protocol.

BMJ Open 2021 Nov 9;11(11):e052449. Epub 2021 Nov 9.

Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Biomedical Research Centre, University of Oxford, Oxford, UK.

Introduction: The Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration of from age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.

Methods And Analysis: Infants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration of EVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin.

Ethics And Dissemination: The study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universität Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study.

Trial Registration Number: NCT04769037.
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http://dx.doi.org/10.1136/bmjopen-2021-052449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8578987PMC
November 2021

Challenges and proposed solutions in making clinical research on COVID-19 ethical: a status quo analysis across German research ethics committees.

BMC Med Ethics 2021 07 19;22(1):96. Epub 2021 Jul 19.

QUEST Center, Berlin Institute of Health (BIH), Berlin, Germany.

Background: In the course of the COVID-19 pandemic, the biomedical research community's attempt to focus the attention on fighting COVID-19, led to several challenges within the field of research ethics. However, we know little about the practical relevance of these challenges for Research Ethics Committees (RECs).

Methods: We conducted a qualitative survey across all 52 German RECs on the challenges and potential solutions with reviewing proposals for COVID-19 studies. We de-identified the answers and applied thematic text analysis for the extraction and synthesis of challenges and potential solutions that we grouped under established principles for clinical research ethics.

Results: We received an overall response rate of 42%. The 22 responding RECs reported that they had assessed a total of 441 study proposals on COVID-19 until 21 April 2020. For the review of these proposals the RECs indicated a broad spectrum of challenges regarding (1) social value (e.g. lack of coordination), (2) scientific validity (e.g. provisional study planning), (3) favourable risk-benefit ratio (e.g. difficult benefit assessment), (4) informed consent (e.g. strict isolation measures), (5) independent review (e.g. lack of time), (6) fair selection of trial participants (e.g. inclusion of vulnerable groups), and (7) respect for study participants (e.g. data security). Mentioned solutions ranged from improved local/national coordination, over guidance on modified consent procedures, to priority setting across clinical studies.

Conclusions: RECs are facing a broad spectrum of pressing challenges in reviewing COVID-19 studies. Some challenges for consent procedures are well known from research in intensive care settings but are further aggravated by infection measures. Other challenges such as reviewing several clinical studies at the same time that potentially compete for the recruitment of in-house COVID-19 patients are unique to the current situation. For some of the challenges the proposed solutions in our survey could relatively easy be translated into practice. Others need further conceptual and empirical research. Our findings together with the increasing body of literature on COVID-19 research ethics, and further stakeholder engagement should inform the development of hands-on guidance for researchers, funders, RECs, and further oversight bodies.
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http://dx.doi.org/10.1186/s12910-021-00666-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287116PMC
July 2021

Implementation of a renal pharmacist consultant service - Information sharing in paper versus digital form.

J Clin Pharm Ther 2021 Jun 20;46(3):838-845. Epub 2021 Feb 20.

Hospital Pharmacy, University Hospital, LMU Munich, Munich, Germany.

What Is Known And Objective: Renal impairment (RI) and renal drug-related problems (rDRP) often remain unrecognized in the community setting. A "renal pharmacist consultant service" (RPCS) at hospital admission can support patient safety by detecting rDRP. However, the efficient information sharing from pharmacists to physicians is still discussed. The aim of the study was to test the implementation of a RPCS and its effectiveness on prescription changes and to evaluate two ways of written information sharing with physicians.

Methods: Urological patients with eGFR of 15-59 ml/min and ≥1 drug were reviewed for manifest and potential rDRP at admission by a pharmacist. Written recommendations for dose or drug adaptation were forwarded to physicians comparing two routes: July-September 2017 paper form in handwritten chart; November 2017-January 2018 digital PDF document in the electronic patient information system and e-mail alert. Prescription changes regarding manifest rDRP were evaluated and compared with a previous retrospective study without RPCS.

Results And Discussion: The RPCS detected rDRP in 63 of 234 (26.9%) patients and prepared written recommendations (median 1 rDRP (1-5) per patient) concerning 110 of 538 (20.5%) drugs at admission. For manifest rDRP, acceptance rates of recommendations were 62.5% (paper) vs 42.9% (digital) (P = 0.16). Compared with the retrospective study without RPCS (prescription changes in 21/76 rDRP; 27.6%), correct prescribing concerning manifest rDRP significantly increased by 27.1%.

What Is New And Conclusion: A RPCS identifies patients at risk for rDRP and significantly increases appropriate prescribing by physicians. In our hospital (no electronic order entry, electronic chart or ward pharmacists), consultations in paper form seem to be superior to a digital PDF document.
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http://dx.doi.org/10.1111/jcpt.13371DOI Listing
June 2021

Implementation of the EU clinical trial regulation transforms the ethics committee systems and endangers ethical standards.

J Med Ethics 2020 Dec 23. Epub 2020 Dec 23.

Centre for Health Ethics, Law and History, Vilnius University Faculty of Medicine, Vilnius, Lithuania.

The upcoming Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use (Regulation), which will replace the current Clinical Trial Directive at the end of 2021, has triggered a significant reform of research ethics committee systems in Europe. Changes related to ethics review of clinical trials in the EU were considered to be essential to create a more favourable environment to conduct clinical trials in the EU. The concern is, however, that the role of the research ethics committees will weaken in at least some of the Member States because the new Regulation allows narrowing down the scope of ethics review as compared with the currently valid Clinical Trial Directive. Although the new Regulation may lead to faster approval procedures for clinical trials, which is especially relevant in the context of pandemics, high-quality ethics reviews integrating methodological aspects of a clinical trial should nevertheless be ensured. To maintain high research ethics standards as well as to foster measures to mitigate potential negative consequences of the reform, it is therefore of vital importance to start debating and sharing the reflections about the potential consequences of these transformations and trends as soon as possible.
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http://dx.doi.org/10.1136/medethics-2020-106757DOI Listing
December 2020

Redundant trials can be prevented, if the EU clinical trial regulation is applied duly.

BMC Med Ethics 2020 10 28;21(1):107. Epub 2020 Oct 28.

Ludwig-Maximilians-University of Munich, The Institute for Medical Information Processing, Biometry, and Epidemiology, and Chairman of the Permanent Working Party of Research Ethics Committees in Germany, Scharnitzerstaße 7, 82166, Gräfelfing, Germany.

The problem of wasteful clinical trials has been debated relentlessly in the medical community. To a significant extent, it is attributed to redundant trials - studies that are carried out to address questions, which can be answered satisfactorily on the basis of existing knowledge and accessible evidence from prior research. This article presents the first evaluation of the potential of the EU Clinical Trials Regulation 536/2014, which entered into force in 2014 but is expected to become applicable at the end of 2021, to prevent such trials. Having reviewed provisions related to the trial authorisation, we propose how certain regulatory requirements for the assessment of trial applications can and should be interpreted and applied by national research ethics committees and other relevant authorities in order to avoid redundant trials and, most importantly, preclude the unnecessary recruitment of trial participants and their unjustified exposure to health risks.
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http://dx.doi.org/10.1186/s12910-020-00536-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592564PMC
October 2020

Impact of the COVID-19 pandemic on clinical trials with drugs.

Authors:
Joerg Hasford

Expert Opin Drug Saf 2020 Nov 8;19(11):1373-1375. Epub 2020 Oct 8.

Institute for Medical Informatics, Biometry and Epidemiology, Ludwigs-Maximilians-Universitaet Muenchen , Muenchen, Germany.

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http://dx.doi.org/10.1080/14740338.2020.1828861DOI Listing
November 2020

Large Simple Double-Blind Randomized Trials for the Rapid Assessment of the Effectiveness of COVID-19 Vaccines.

Authors:
Joerg Hasford

J Infect Dis 2020 10;222(9):1571-1572

Institute for Medical Information Processing, Biometry, and Epidemiology, University of Munich, Munich, Germany.

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http://dx.doi.org/10.1093/infdis/jiaa456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499599PMC
October 2020

Correct use of non-indexed eGFR for drug dosing and renal drug-related problems at hospital admission.

Eur J Clin Pharmacol 2020 Dec 10;76(12):1683-1693. Epub 2020 Jul 10.

Hospital Pharmacy, University Hospital, LMU Munich, Marchioninistr. 15, 81377, Munich, Germany.

Purpose: Two to seven percent of the German adult population has a renal impairment (RI) with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m. This often remains unrecognized and adjustment of drug therapy is lacking. To determine renal function in clinical routine, the CKD-EPI equation is used to calculate an indexed eGFR (ml/min/1.73m). For drug dosing, it has to be individualized to a non-indexed eGFR (ml/min) by the patient's body surface area. Here, we investigated the number of patients admitted to urological wards of a teaching hospital with RI between July and December 2016. Additionally, we correctly used the eGFR for drug and dosage adjustments and to analyse the use of renal risk drugs (RRD) and renal drug-related problems (rDRP).

Methods: In a retrospective observational study, urological patients with pharmacist-led medication reconciliation at hospital admission and eGFR (CKD-EPI) of 15-59 ml/min/1.73m were identified. Indexed eGFR (ml/min/1.73m) was recalculated with body surface area to non-indexed eGFR (ml/min) for correct drug dosing. Medication at admission was reviewed for RRD and based on the eGFR for rDRP, e.g. inappropriate dose or contraindication.

Results: Of 1320 screened patients, 270 (20.5%) presented with an eGFR of 15-59 ml/min/1.73m. After readjustment, 203 (15.4%) patients had an eGFR of 15-59 ml/min. Of these, 190 (93.6%) used ≥ 1 drugs at admission with 660 of 1209 (54.7%) drugs classified as RRD. At least one rDRP was identified in 115 (60.5%) patients concerning 264 (21.8%) drugs.

Conclusion: Renal impairment is a common risk factor for medication safety in urologic patients admitted to a hospital. Considerable shifts were seen in eGFR-categories when correctly calculating eGFR for drug dosing purposes. The fact that more than half of the study patients showed rDRP at hospital admission underlines the need to consider this risk factor appropriately.
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http://dx.doi.org/10.1007/s00228-020-02953-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7661404PMC
December 2020

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia.

Leukemia 2020 08 29;34(8):2138-2149. Epub 2020 Jun 29.

Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie - IBE, Ludwig-Maximilians Universität, Munich, Germany.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
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http://dx.doi.org/10.1038/s41375-020-0931-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387299PMC
August 2020

Erratum zu: Arzneimittelprüfung an nicht einwilligungsfähigen Erwachsenen: Kritische Bewertung der neuen gesetzlichen Regelung durch medizinische Ethikkommissionen in Deutschland.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020 Oct;63(10):1297-1298

Unité d'Éthique Clinique, Universitätsklinikum Lausanne (CHUV), Universität Lausanne, Lausanne, Schweiz.

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http://dx.doi.org/10.1007/s00103-020-03129-4DOI Listing
October 2020

[Critical evaluation of the new legal regulation of pharmaceutical trials with adults who lack decision-making capacity: a survey of human research ethics committees in Germany].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2020 Apr;63(4):465-474

Unité d'Éthique Clinique, Universitätsklinikum Lausanne (CHUV), Universität Lausanne, Lausanne, Schweiz.

Background: In Germany, the drug law was revised in 2016 to include new regulations on clinical drug trials with adults who lack decision-making capacity. For the first time, trials with a merely indirect benefit (benefit for other patients with similar characteristics) will be possible if several safeguards are respected. The ethical justification and practicality of this regulation are controversially discussed.

Objectives: (1) Eliciting the current pertinent practice of research ethics committees in Germany regarding research with indirect benefit on adults without decision-making capacity; (2) exploring the possibilities and difficulties of implementing the new law.

Methods: Semiquantitative, anonymous questionnaire among 249 members of all 53 human research ethics committees in Germany.

Results: Eighty-four questionnaires were analyzed (response rate 34%). The participants disagreed on assigning research projects to the categories of research with direct benefit to the subject, with an indirect benefit, and without any benefit. Moreover, the criteria of minimum risk and minimum burden were interpreted heterogeneously. More than half of the participants judged the newly introduced research advance directive to be unnecessary, given the legal safeguards in place. The applicability of these directives was doubted because of the strict requirements for anticipatory informed consent and the restricted predictability of future research.

Conclusion: In spite of the new legal regulation, significant ethical uncertainties remain concerning research with indirect benefit on adults without decision-making capacity. It remains an open question whether we need a better explanation of the law, additional legal regulation, practice evaluation, or a completely new law.
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http://dx.doi.org/10.1007/s00103-019-03058-xDOI Listing
April 2020

Prognosis of patients with chronic myeloid leukemia presenting in advanced phase is defined mainly by blast count, but also by age, chromosomal aberrations and hemoglobin.

Am J Hematol 2019 11 14;94(11):1236-1243. Epub 2019 Sep 14.

Institute for Medical Information Processing, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany.

Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.
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http://dx.doi.org/10.1002/ajh.25628DOI Listing
November 2019

[Quality and Structure of Outpatient Care for Adults with ADHD (Attention Deficit Hyperactivity Disorder) - Results of the RAABE-Study [Retrospective Data Analysis of ADHD Treatment in Adults]].

Psychiatr Prax 2019 Sep 13;46(6):317-323. Epub 2019 Aug 13.

Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität München.

Objective: Data on the quality and structure of outpatient care for adults with ADHD in Germany are scarce. The study describes the reality of care and identifies possible measures for improvement.

Method: A complete survey of adults ≥ 18 years of age with a diagnosis of ADHD (ICD-Code F90.0) covered by statutory health insurance was carried out in the outpatient setting in the German Free State of Bavaria in 2012.

Results: The analysis revealed a diagnostic prevalence of ADHD in adults in Bavaria of 0.1 %, which was lower than expected based on ADHD prevalence estimates in the general population (about 3 %). Patients were diagnosed by specialists for CNS disorders and by general practitioners. About 30 % of patients received a medication approved for the treatment of ADHD, and these were in approx. 75 % of cases prescribed by specialists for CNS disorders. About 50 % of the patients received psychotherapy.

Conclusion: General practitioners play an important role for medical care of adult patients with ADHD. Continuous medical education programmes and collaboration between general practitioners and specialists is an urgent imperative for improving outpatient care of ADHD in adults.
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http://dx.doi.org/10.1055/a-0880-1804DOI Listing
September 2019

Differences in treatment and monitoring of chronic myeloid leukemia with regard to age, but not sex: Results from a population-based study.

Eur J Haematol 2019 Oct 28;103(4):362-369. Epub 2019 Aug 28.

Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

There are established guidelines for treatment and monitoring of chronic myeloid leukemia (CML) but little is known about routine care. Data on ICD-10 codes as well as prescribed medications were available for 10.5 million patients in the statutory health insurance system in Bavaria for the years 2010 to 2016. Also, data on the molecular and cytogenetic monitoring were integrated. A total of 1714 adult patients with CML were observed. Only 50.8% received more than 67.5 daily doses per quarter year (target: 91.5) while 18.2% did not receive any tyrosine kinase inhibitor (TKI). The median number of daily doses was at least 80 doses per quarter year for all age groups in men, but decreased to 62 doses in elderly women. With this exception, no differences between men and women were observed. The percentage of patients without any TKI increased with age. The median number of molecular examinations was 3.54 independent of age and sex. Even in a highly developed country, still a considerable number of patients with CML seem to not receive adequate treatment, whereas molecular monitoring can be considered satisfactory.
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http://dx.doi.org/10.1111/ejh.13293DOI Listing
October 2019

Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol.

BMJ Open 2019 06 28;9(6):e028578. Epub 2019 Jun 28.

Centre for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

Introduction: The POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes.

Methods And Analysis: Infants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes.

Ethics And Dissemination: The study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial.

Trial Registration Number: NCT03364868.
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http://dx.doi.org/10.1136/bmjopen-2018-028578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609035PMC
June 2019

[Medical research ethics committees in the Federal Republic of Germany: establishment and integration into medical research].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Jun;62(6):682-689

Arbeitskreis Medizinischer Ethik-Kommissionen in der Bundesrepublik Deutschland e. V., Gräfelfing, Gräfelfing, Deutschland.

In Germany, the only research ethics committees (RECs) that are entitled to assess all fields of biomedical research are those set up according to state law by faculties of medicine, medical associations or state authorities. In a multidisciplinary review, research projects are evaluated against the criteria of "scientific quality," "conformity with law" and "ethical and medical acceptability."Since 2004, the "favourable opinion" of an REC and the approval by the competent federal drug authority, jointly constitute a legal condition to conduct drug trials. As a consequence of EU Regulation 536/2014, the importance of the decision of an REC for drug research will be diminished. For all other fields of biomedical research that are not covered by legislation, as is the case in drug research or in research with medical devices, the opinion of an REC is only considered as legally non-binding advice for the researcher.The local, independent RECs established the "Permanent Working Party of German Research Ethics Committees" to share experiences, to harmonise their work and to establish partnership with the public. This working party functions similarly to national research ethics committees in other states.
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http://dx.doi.org/10.1007/s00103-019-02950-wDOI Listing
June 2019

Screening for asymptomatic β-cell autoimmunity in young children.

Lancet Child Adolesc Health 2019 05 10;3(5):288-290. Epub 2019 Feb 10.

DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, Technical University of Dresden, Dresden, Germany.

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http://dx.doi.org/10.1016/S2352-4642(19)30028-8DOI Listing
May 2019

Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Haematologica 2019 05 4;104(5):955-962. Epub 2018 Dec 4.

Medizinische Klinik III, Universität München, Germany.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at .
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http://dx.doi.org/10.3324/haematol.2018.206797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518910PMC
May 2019

Blood draws up to 3% of blood volume in clinical trials are safe in children.

Acta Paediatr 2019 05 30;108(5):940-944. Epub 2018 Oct 30.

Institute of Diabetes Research, Helmholtz Zentrum München and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany.

Aim: Recommendations for maximum blood draw in children range from 1 to 5% despite limited evidence. The aim of the study was to assess the safety of blood draws in children aged six months to 12 years targeting volumes of 3% of total blood volume.

Methods: Children who experienced three-monthly blood draws during participation in one of three investigators initiated clinical trials conducted in our institution were examined. In total, 629 venous blood draws were performed in 141 children. Adverse events and blood counts were assessed.

Results: Overall, 608 adverse events were reported. None of these included symptoms that reflected concerns on blood draw volumes or frequency. Anaemia and red cell or haemoglobin measurements outside the normal age range were not observed. A reduction in haemoglobin, haematocrit, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration and mean corpuscular volume was noted in children participating in one of the three trials analysed.

Conclusion: Regular blood draws of up to 3% of total blood volume were not associated with signs of anaemia or hypovolaemia in young children. We suggest that the European recommendations be revised for clinical studies in which children are not exposed to treatments that are associated with anaemia risk.
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http://dx.doi.org/10.1111/apa.14607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587985PMC
May 2019

Defining therapy goals for major molecular remission in chronic myeloid leukemia: results of the randomized CML Study IV.

Leukemia 2018 05 26;32(5):1222-1228. Epub 2018 Feb 26.

Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, Ludwig-Maximilians-Universität, München, Germany.

Major molecular remission (MMR) is an important therapy goal in chronic myeloid leukemia (CML). So far, MMR is not a failure criterion according to ELN management recommendation leading to uncertainties when to change therapy in CML patients not reaching MMR after 12 months. At monthly landmarks, for different molecular remission status Hazard ratios (HR) were estimated for patients registered to CML study IV who were divided in a learning and a validation sample. The minimum HR for MMR was found at 2.5 years with 0.28 (compared to patients without remission). In the validation sample, a significant advantage for progression-free survival (PFS) for patients in MMR could be detected (p-value 0.007). The optimal time to predict PFS in patients with MMR could be validated in an independent sample at 2.5 years. With our model we provide a suggestion when to define lack of MMR as therapy failure and thus treatment change should be considered. The optimal response time for 1% BCR-ABL at about 12-15 months was confirmed and for deep molecular remission no specific time point was detected. Nevertheless, it was demonstrated that the earlier the MMR is achieved the higher is the chance to attain deep molecular response later.
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http://dx.doi.org/10.1038/s41375-018-0055-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940636PMC
May 2018

Efficacy of vildagliptin for prevention of postpartum diabetes in women with a recent history of insulin-requiring gestational diabetes: A phase II, randomized, double-blind, placebo-controlled study.

Mol Metab 2018 03 3;9:168-175. Epub 2018 Jan 3.

Forschergruppe Diabetes e.V. am Helmholtz Zentrum München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany; Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany. Electronic address:

Objective: Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes.

Methods: Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT).

Results: Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2-10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15-7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26-1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events.

Conclusions: The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and β-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. TRIAL REGISTRATION NUMBER AT CLINICALTRIALS.GOV: NCT01018602.
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http://dx.doi.org/10.1016/j.molmet.2017.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869734PMC
March 2018

Erratum to: Ethical aspects of clinical trials in rare diseases.

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2017 08;60(8):893

Institut für Biometrie, Medizinische Hochschule Hannover, Hannover, Germany.

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http://dx.doi.org/10.1007/s00103-017-2588-8DOI Listing
August 2017

[The impact of the EU Regulation 536/2014 on the tasks and functioning of ethics committees in Germany].

Authors:
Joerg Hasford

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2017 Aug;60(8):830-835

Arbeitskreis Medizinischer Ethik-Kommissionen in der Bundesrepublik Deutschland e. V., Scharnitzer Straße 7, 82166, Gräfelfing, Deutschland.

The EU Clinical Trial Regulation 536/2014 (CTR) and its implementation in Germany led to substantial changes of the established, well-accepted and effective system of reviewing clinical trial applications by ethics committees (ECs), which impair their independence. For the first time, the German federal legislator specified in detail the composition, functioning, tasks and responsibilities of ECs. ECs have to be registered with the federal drug authority BfArM and if an EC does not perform properly the registration can be withdrawn. In addition, the drug authorities may override the negative opinion expressed by an EC. The ECs will also lose their financial autonomy as the fees will be fixed by the federal government. The tasks and responsibilities of the ECs remain almost entirely unchanged, however. The ECs remain involved in the assessment of both parts of the application dossier. Part I is assessed together with the drug authorities, the drug authorities having the lead. The assessment of part II remains the sole responsibility of the EC. As the deadlines for the assessment became rather short, in particular for multinational trials, and the communication with the sponsor will be in writing only, the established procedures of ECs have to be modified. Up to now it was common to verbally discuss problematic issues with the sponsor. The CTR is focused on written communication with the sponsor via the EU portal. ECs, their office staff and chairpersons will need considerable professionalism and respective training. The future workflow requires substantial IT support. The ECs and the Association of Medical Ethics Committees in Germany will do their utmost to protect efficiently the research subjects and to promote Germany as a major destination for clinical research.
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http://dx.doi.org/10.1007/s00103-017-2580-3DOI Listing
August 2017

Factors influencing adherence in CML and ways to improvement: Results of a patient-driven survey of 2546 patients in 63 countries.

J Cancer Res Clin Oncol 2017 Jul 13;143(7):1167-1176. Epub 2017 Mar 13.

Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet, Munich, Germany.

Optimal adherence to CML therapy is of key importance to maximize treatment effectiveness. Two clinical studies (ADAGIO and Hammersmith) have proven a clear correlation between adherence and achieving optimal treatment response and have revealed that non-adherence is common in CML patients (Marin et al. in J Clin Oncol 28(24):2381-2388, 2010, Noens et al. in Haematologica 99(33):437-447, 2014). The aim of this study is to assess the extent of suboptimal adherence and to investigate motivations and behavioural patterns of adherence in a worldwide patient sample. Questionnaires were provided by the CML Advocates Network and were filled in by patients online and offline. Patient characteristics, treatment and motivations were collected. Adherence was assessed by the 8-item Morisky Medication Adherence scale. Logistic regression models were fitted to investigate the influence of different factors on adherence. Overall, 2 546 questionnaires from 63 countries and 79 CML patient organisations were evaluable. 32.7% of participants were highly adherent, 46.5% were in the medium and 20.7% in the low adherence group. Factors increasing the probability of being in the high adherence group are older age, male sex, management of side effects, only one tablet per day and feeling well informed about CML by the doctor. More than 2 years since diagnosis were significantly lowering the chance as was the use of reminding tools. Living arrangements, multiple medication and personal payment obligations increased the probability to be at least in the medium adherent group. This is the most comprehensive study conducted to date to gain knowledge about factors causing non-adherence in CML. Better information on the disease, medication and management of side effects, supported by haematologists, is key to improve adherence.
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http://dx.doi.org/10.1007/s00432-017-2372-zDOI Listing
July 2017

Systematic review and meta-analysis of standard-dose imatinib vs. high-dose imatinib and second generation tyrosine kinase inhibitors for chronic myeloid leukemia.

J Cancer Res Clin Oncol 2017 Jul 8;143(7):1311-1318. Epub 2017 Mar 8.

Medizinische Fakultaet Mannheim, Universität Heidelberg, Heidelberg, Germany.

Purpose: Most randomized clinical trials evaluating second generation tyrosine kinase inhibitors (TKI) for the first-line treatment of Chronic Myeloid Leukemia used as comparator the 'standard' dose of 400 mg imatinib daily. Several studies showed higher rates of major molecular remission (MMR) at 12 months with 800 mg compared to 400 mg, suggesting that high-dose imatinib may be the appropriate comparator rather than 400 mg.

Methods: We systematically reviewed randomized trials comparing the two dosages, calculated a common estimator and compared the result to a common estimator of trials evaluating a second generation TKI in comparison with 400 mg imatinib daily.

Results: We identified three trials comparing 400-800 mg imatinib resulting in a common relative risk of 1.30 (1.13-1.49) and indicating a significantly higher rate of MMR in patients treated with 800 mg imatinib (p = 0.0003). We identified five trials comparing 400 mg imatinib daily to a second generation TKI. The common relative risk for MMR at 12 months was 1.69 (1.50-1.90, p < 0.0001). Differences in the prognostic profiles precluded a direct comparison of the common efficacy estimates.

Conclusions: We conclude that imatinib was probably not licensed at the optimal dose initially. We suggest that in the future, new TKIs are compared with a higher dose of imatinib. In addition, high-dose imatinib should be considered more often for routine clinical decisions based on the characteristics of the individual patient.
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http://dx.doi.org/10.1007/s00432-017-2385-7DOI Listing
July 2017

[Ethical aspects of clinical trials in rare diseases].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2017 May;60(5):556-562

Institut für Biometrie, Medizinische Hochschule Hannover, Hannover, Deutschland.

It is estimated that there are about four million people suffering from rare diseases in Germany. For roughly the last 20 years, there has been an increasing interest in therapeutic research for rare diseases. Drug research is highly regulated via numerous laws, regulations and ethical conventions that do not offer any waivers for clinical trials in rare diseases. Thus the ethical assessment of the clinical trial application for a rare disease is basically the same as for a common disease. As the ethical standards of clinical research, for example regarding informed consent, are derived from constitutional rights and have been codified in the German drug law, it is no surprise that they cannot depend on the frequency of a disease. A very important aspect of the ethical assessment is the biometric quality with regard to study design, sample size estimation and statistical analysis, as methodologically poor research with humans is per se unethical. Problems with sample size estimations and pilot studies will be addressed in more detail. Pilot studies should be avoided and sample size estimations should not assume overoptimistic effect sizes and should not increase the error probability beyond 5% two-sided.
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http://dx.doi.org/10.1007/s00103-017-2537-6DOI Listing
May 2017

Smokers with chronic myeloid leukemia are at a higher risk of disease progression and premature death.

Cancer 2017 Jul 13;123(13):2467-2471. Epub 2017 Feb 13.

Institute for Medical Information Sciences, Biometry, and Epidemiology (IBE), Ludwig-Maximilians University, Munich, Germany.

Background: Smoking is suspected to not only be a risk factor for chronic myeloid leukemia but an adverse prognostic factor for the disease as well. The objective of the current study was to investigate the impact of smoking on survival and progression to advanced phases of disease.

Methods: Based on the data of the German CML Study IV, the authors analyzed the effect of smoking using a multivariate Cox model with the addition of the European Treatment and Outcome Study (EUTOS) long-term survival score variables of age, spleen size, thrombocytes, and peripheral blasts as well as sex, comorbidities, and type of treatment center.

Results: The 8-year survival probability was 87% for a nonsmoking patient and 83% for a patient who smoked. The authors noted a 2.08-times higher risk of death for smokers in comparison with nonsmokers and a 2.11-times higher cause-specific hazard of disease progression. An interaction between smoking and age was found in the model for survival. No significant difference with regard to molecular response was observed.

Conclusions: Even when considering differences in socioeconomic status and lifestyle between patients who smoke and nonsmokers, the current analysis demonstrated that smoking also might affect disease biology. The results of the current study indicate that patients with chronic myeloid leukemia, in particular those aged <60 years, should be encouraged to quit smoking. Cancer 2017;123:2467-71. © 2017 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30636DOI Listing
July 2017

No influence of BCR-ABL1 transcript types e13a2 and e14a2 on long-term survival: results in 1494 patients with chronic myeloid leukemia treated with imatinib.

J Cancer Res Clin Oncol 2017 May 12;143(5):843-850. Epub 2017 Jan 12.

Institute of Hematology and Oncology "L. and A. Seràgnoli", S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.

Purpose: The genomic break on the major breakpoint cluster region of chromosome 22 results in two BCR-ABL1 transcripts of different sizes, e14a2 and e13a2. Favorable survival probabilities of patients with chronic myeloid leukemia (CML) in combination with too small patient samples may yet have obstructed the observation of differences in overall survival of patients according to transcript type. To overcome potential power problems, overall survival (OS) probabilities and probabilities of CML-related death were analyzed in 1494 patients randomized to first-line imatinib treatment.

Methods: OS probabilities and probabilities of dying of CML were compared using the log-rank or Gray test whichever was appropriate. Both tests were stratified for the EUTOS long-term survival score.

Results: Between the groups with a single transcript, neither OS probabilities (stratified log-rank test: p = 0.106) nor probabilities of CML-related death were significantly different (stratified Gray test: p = 0.256). Regarding OS, the Cox hazard ratio (HR) of transcript type e13a2 (n = 565) to type e14a2 (n = 738) was 1.332 (95% CI 0.940-1.887). Considering probabilities of leukemia-related death, the corresponding subdistribution HR resulted in 1.284 (95% CI 0.758-2.176). Outcome did not change if patients with both transcripts (n = 191) were added to the 738 with type e14a2 only.

Conclusions: The prognostic association of transcript type and long-term survival outcome was weak and without clinical relevance. However, earlier reported differences in the rate and the depth of molecular response could be relevant for the chance of successfully discontinuing TKI treatment. The effect of transcript type on molecular relapse after discontinuation is unknown, yet.
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http://dx.doi.org/10.1007/s00432-016-2321-2DOI Listing
May 2017

Improved survival boosts the prevalence of chronic myeloid leukemia: predictions from a population-based study.

J Cancer Res Clin Oncol 2016 Jul 16;142(7):1441-7. Epub 2016 Apr 16.

Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität, Marchioninistr. 15, 81377, Munich, Germany.

Purpose: Due to prolonged survival, there will be many more chronic myeloid leukemia (CML) patients alive in the future. The aims of this work were to estimate the current prevalence of CML by using routine data and to project future patient numbers in Germany.

Methods: Data were available for about 10.5 million people in the statutory health insurance system in Bavaria for the years 2008-2013. Survival rates were adapted from two recent publications.

Results: The mean estimated age-standardized (Old European Standard Population) incidence rates per 100,000 inhabitants were 1.300 and 1.768 for women and men. Based on the population data, we estimated a total number of about 9000 CML patients in Germany for 2012. We expect the number of CML patients to increase further until at least 2040-2050 with a maximum of more than 20,000 CML patients as the most probable scenario.

Conclusions: Using a restrictive definition for case patients, we do not think that there is much overestimation. As a consequence of this considerable increase of the prevalence of CML the burden for the health care system will increase with respect to costs and medical care needed. The procedure presented here allows to estimate the expected number of CML patients in other countries, too.
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http://dx.doi.org/10.1007/s00432-016-2155-yDOI Listing
July 2016

Tiotropium Respimat(®) vs. HandiHaler(®): real-life usage and TIOSPIR trial generalizability.

Br J Clin Pharmacol 2016 Feb 23;81(2):379-88. Epub 2015 Dec 23.

Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universitaet Muenchen, Munich, Germany.

Aim: Two inhaler devices (Respimat® and HandiHaler®) are available for tiotropium, a long acting anticholinergic agent. We aimed to analyze drug utilization, off-label usage and generalizability of the TIOSPIR trial results for both devices.

Methods: Patients aged ≥18 years exhibiting at least one documented prescription of tiotropium in the database of the Association of Statutory Health Insurance Physicians, Bavaria, Germany, were included (years 2004-2008). Annual period prevalence rates (PPRs) were calculated stratified by age, gender and inhaler devices. Off-label usage (patients lacking a chronic obstructive pulmonary disease (COPD) diagnosis) and the proportion of patients meeting the inclusion and exclusion criteria of the TIOSPIR trial were analyzed.

Results: Between 2004 and 2008, PPRs increased and varied between 49.2 and 74.5 per 10 000 persons for HandiHaler® and between 1.5 and 9.3 per 10 000 persons for Respimat®. Small differences regarding patient characteristics existed between the two inhaler devices. Only about 30% (HandiHaler® 32.1%, Respimat® 30.0%) of the database patients receiving tiotropium could be theoretically included in the TIOSPIR trial.

Conclusions: Comparing the two tiotropium devices, no clinically relevant differences regarding patient and prescribing characteristics were revealed. Results of the TIOSPIR trial were generalizable only to a minority of our study patients, underlining the need for real-life data.
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http://dx.doi.org/10.1111/bcp.12808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833170PMC
February 2016
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