Four reasons why too many informed consents to clinical research are invalid: a critical analysis of current practices.

OBJECTIVE: Informed consent (IC) is a central ethical and legal requirement for clinical research that aims to protect the autonomy of participants. To enable an autonomous decision and valid consent, adequate understanding must be ensured. However, a considerable proportion of participants do not understand the relevant aspects about participation in research, for example, approximately 45% could not name at least one risk. As such, the inadequate understanding of IC has been known for several decades, and it still constitutes a severe problem for the ethical conduct of research. Through delineating the most pressing deficits of current IC procedures that lead to insufficient understanding, we aim to encourage the discussion among stakeholders, for example, clinical researchers, and to provide the grounds for practical solutions. MAIN ARGUMENTS: (1) IC documents are too long to be read completely, thus, make it very difficult for potential participants to identify the material facts about the trial. (2) The low readability of the IC documents disadvantages persons with limited literacy. (3) The therapeutic misconception frequently prevents participants to realise that the primary purpose of clinical research is to benefit future patients. (4) Excessive risk disclosures, insufficient information about expected benefits and framing effects compromise a rational risk/benefit assessment. CONCLUSION: Due to these deficits, practices of IC in clinical research too often preclude adequate understanding of prospective participants, thus, invalidating IC. The gap between the well-specified ethical norm to enable IC and its insufficient translation into practice can no longer be accepted, as participant rights and the public trust in responsible research are at stake. Hence, immediate action is needed to address the prevailing deficits.

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

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 Bifidobacterium infantis 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 B. infantis 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.

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

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.

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

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 eGFRnon-indexed 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.

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

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.

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

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.

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

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/1.73m2. 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/1.73m2). 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 eGFRnon-indexed 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 eGFRindexed (CKD-EPI) of 15-59 ml/min/1.73m2 were identified. Indexed eGFR (ml/min/1.73m2) 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 eGFRnon-indexed for rDRP, e.g. inappropriate dose or contraindication. RESULTS: Of 1320 screened patients, 270 (20.5%) presented with an eGFRindexed of 15-59 ml/min/1.73m2. After readjustment, 203 (15.4%) patients had an eGFRnon-indexed 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 eGFRnon-indexed 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.

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

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.

[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]. / Arzneimittelprüfung an nicht einwilligungsfähigen Erwachsenen: Kritische Bewertung der neuen gesetzlichen Regelung durch medizinische Ethikkommissionen in Deutschland.

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.

[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]]. / Qualität und Struktur der ambulanten Versorgung von erwachsenen Patienten mit ADHS (Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung).

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.

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.

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.

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

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.

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.

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.

[Medical research ethics committees in the Federal Republic of Germany: establishment and integration into medical research]. / Medizinische Ethikkommissionen in der Bundesrepublik Deutschland: Entstehung und Einbindung in die medizinische Forschung.

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.

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

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.

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.

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 ß-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.