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ZusammenfassungMit der Implementierung der neuen EU-Verordnung 536/2014 (Clinical Trials Regulation – CTR) zum 31.01.2022 sollen Genehmigung und Durchführung klinischer Prüfungen mit Humanarzneimitteln innerhalb der Europäischen Union (EU) harmonisiert werden. Die Genehmigung erfolgt über das elektronische Portal CTIS (Clinical Trials Information System) der Europäischen Arzneimittel-Agentur (EMA). Neben kommerziellen Sponsoren sind im Rahmen von wissenschaftsinitiierten klinischen Prüfungen (IIT) auch Sponsoren an akademischen Einrichtungen von der Implementierung der CTR betroffen. Zahlreiche Änderungen in der Prozesslandkarte für regulierte Arzneimittelstudien sind notwendig.Neue Aspekte betreffen die generelle Nutzerstruktur und das Rechtekonzept des CTIS. Anforderungen, die bislang nur für Prüfpräparate/Placebo galten, gelten nun auch für Hilfspräparate. In der EU noch nicht zugelassene Prüf- und Hilfspräparate müssen in der Arzneimitteldatenbank XEVMPD registriert werden. Weitere wesentliche Neuerungen sind die Meldung von „schwerwiegenden Verstößen“, die Veröffentlichung relevanter Studiendokumente, die Einführung einer „laienverständlichen Zusammenfassung“, die Archivierungsdauer von 25 Jahren, das Konzept der „minimalinterventionellen klinischen Prüfung“ und die Möglichkeit einer Co-Sponsorenschaft.Die ersten Erfahrungen bei der Antragstellung zeigen, dass das neue System noch weiter verbessert werden muss. Dies betrifft z. B. die EU-weite Harmonisierung der Anforderungen und die Behebung technischer Mängel. Mittel- und langfristig dürften aber Erleichterungen in Bezug auf regulatorische Prozesse spürbar sein. Hier sind intensivierte Absprachen mit nationalen Oberbehörden und Ethikkommissionen, effektives Wissensmanagement und verbesserte Kommunikation gefragt.

With the implementation of the new EU Regulation 536/2014 (Clinical Trials Regulation - CTR) on 31 January 2022, the approval and conduct of clinical trials with medicinal products for human use are to be harmonized within the European Union (EU). Approval is granted via the electronic Clinical Trials Information System (CTIS) portal of the European Medicines Agency (EMA). In addition to commercial sponsors, sponsors at academic institutions are also affected by the implementation of the CTR in the context of investigator-initiated clinical trials (IITs). Numerous changes in the process map for regulated drug trials are necessary.New aspects concern the general user structure and the role and permission concept of CTIS. Requirements that previously applied only to investigational medicinal products/placebo now also apply to auxiliary medicinal products. Investigational and auxiliary medicinal products not yet approved in the EU must be registered in the XEVMPD drug database. Other significant changes include the reporting of "serious breaches," the publication of relevant study documents, the introduction of a "summary in layman's terms," the archiving period of 25 years, the implementation of "low intervention clinical trials," and the possibility of co-sponsorship.First experience with the application process shows that the new system needs to be further improved. This concerns, for example, the EU-wide harmonization of requirements and the elimination of technical deficiencies. In the medium and long term, however, simplifications with regard to regulatory processes should be noticeable. What is needed here are intensified agreements with national higher authorities and ethics committees, effective knowledge management, and improved communication.Mit der Implementierung der neuen EU-Verordnung 536/2014 (Clinical Trials Regulation – CTR) zum 31.01.2022 sollen Genehmigung und Durchführung klinischer Prüfungen mit Humanarzneimitteln innerhalb der Europäischen Union (EU) harmonisiert werden. Die Genehmigung erfolgt über das elektronische Portal CTIS (Clinical Trials Information System) der Europäischen Arzneimittel-Agentur (EMA). Neben kommerziellen Sponsoren sind im Rahmen von wissenschaftsinitiierten klinischen Prüfungen (IIT) auch Sponsoren an akademischen Einrichtungen von der Implementierung der CTR betroffen. Zahlreiche Änderungen in der Prozesslandkarte für regulierte Arzneimittelstudien sind notwendig.Neue Aspekte betreffen die generelle Nutzerstruktur und das Rechtekonzept des CTIS. Anforderungen, die bislang nur für Prüfpräparate/Placebo galten, gelten nun auch für Hilfspräparate. In der EU noch nicht zugelassene Prüf- und Hilfspräparate müssen in der Arzneimitteldatenbank XEVMPD registriert werden. Weitere wesentliche Neuerungen sind die Meldung von „schwerwiegenden Verstößen“, die Veröffentlichung relevanter Studiendokumente, die Einführung einer „laienverständlichen Zusammenfassung“, die Archivierungsdauer von 25 Jahren, das Konzept der „minimalinterventionellen klinischen Prüfung“ und die Möglichkeit einer Co-Sponsorenschaft.Die ersten Erfahrungen bei der Antragstellung zeigen, dass das neue System noch weiter verbessert werden muss. Dies betrifft z. B. die EU-weite Harmonisierung der Anforderungen und die Behebung technischer Mängel. Mittel- und langfristig dürften aber Erleichterungen in Bezug auf regulatorische Prozesse spürbar sein. Hier sind intensivierte Absprachen mit nationalen Oberbehörden und Ethikkommissionen, effektives Wissensmanagement und verbesserte Kommunikation gefragt.

Human fingertips can regenerate functionally and cosmetically excellent skin and soft tissues. Physiological conditions suppress scar formation and are thus a prerequisite for regenerative healing. Self-adhesive film dressings can provide such favorable conditions. The semi-occlusive treatment is superior to surgery. However, standard dressings leak malodorous wound fluid eventually until the wound is dry. Therefore, we developed and tested a silicone finger cap that forms a mechanically protected, wet chamber around the injury. Its puncturable reservoir allows access to the wound fluid for diagnostic and research purposes and the delivery of pro-regenerative drugs in the future.Patients2 years with full-thickness fingertip injuries unsuitable for simple primary closure were randomized to start treatment with either the film dressing or the silicone finger cap. After 2 weeks, we changed to the other treatment. Patients' choice on the preferred treatment after 4 weeks was the primary outcome parameter. Additionally, we monitored adverse events, unplanned visits, tissue gain, functionality, cosmetic outcome, and quality of life.We randomized 11 patients 2 to 72 years to each group. Eighteen to 20 (90%, intention-to-treat) patients preferred the finger cap. All patients were satisfied with the cosmetic outcome, 88.9% had no disturbing sensibility changes, and 73.7% could report no distortion in the finger's daily use. Epithelialization took between 5 weeks for Allen II and up to 9 weeks in Allen IV injuries. There were 19 device-related adverse events under film dressing and 13 under the finger cap. There were neither severe adverse device effects nor unexpected severe adverse device effects.Employing the summative or synthetic primary endpoint "patient decision for one or the other procedure," our pseudocross-over-designed RCT succeeded in statistically significantly demonstrating the superiority of the silicone finger cap over conventional film therapy. The finger cap was safe and effective, reaching excellent results on all treated injuries without any need for disinfection, antibiotics, shortening of protruding bones, or treatment of hypergranulations. Distal to the tendon insertions, we did not see any limitations regarding injury mechanism, amputation plane, or patients' age.

Postpancreatectomy haemorrhage (PPH) is a rare but potentially fatal complication after pancreatoduodenectomy. Preventive strategies are lacking with scarce data for support. The aim of this study was to investigate whether a prophylactic falciform ligament wrap around the hepatic and gastroduodenal artery can prevent PPH from these vessels.In a randomized, controlled, multicentre trial, patients who were scheduled for elective open partial pancreatoduodenectomy with pancreatojejunostomy between 5 November 2015 and 2 April 2020 were randomly allocated in a 1 : 1 ratio to undergo pancreatoduodenectomy with (intervention) or without (control) a falciform ligament wrap around the hepatic artery. The primary endpoint was the rate of clinically relevant PPH from the hepatic artery or gastroduodenal artery stump within 3 months after pancreatoduodenectomy. Secondary endpoints were the rates of associated postoperative complications, for example postoperative pancreatic fistula (POPF) and PPH.Altogether, 445 patients were randomized with 222 and 223 in each group. Among the patients included in modified intention-to-treat analysis (207 in the intervention group and 210 in the control group), the primary endpoint was observed in six of 207 in the intervention group compared with 15 of 210 in the control group (2.9 versus 7.1 per cent respectively; odds ratio 0.39 (95 per cent c.i. 0.15 to 1.02); P = 0.071). Per protocol analysis showed a significant reduction in the intervention group (odds ratio 0.26 (95 per cent c.i. 0.09 to 0.80); P = 0.017). A soft pancreas texture (43 per cent) and the rate of a clinically relevant POPF were evenly (20 per cent) distributed between the groups. The rate of any clinically relevant PPH including the primary endpoint and other bleeding sites was not significantly different between intervention and control groups (9.7 versus 14.8 per cent respectively).A falciform ligament wrap may reduce PPH from the hepatic artery or gastroduodenal artery stump and should be considered during pancreatoduodenectomy.NCT02588066 (http://www.clinicaltrials.gov).

The primary objective of the IMPRESS study is to assess the causal effects of the IQM peer review on mortality in patients ventilated > 24 h. Secondary analyses are conducted for mortality in patients with myocardial infarction, stroke, COPD, pneumonia, and the procedural provision of a colorectal resection. This article provides a description of the study design and presents baseline results. Descriptive statistics for 231 included hospitals and patient characteristics. Due to randomization, the treatment/control group hospitals were similar with respect to the mortality in patients ventilated > 24 h and other patient and hospital characteristics at baseline. Mortality was highest (lowest) in patients ventilated > 24 h (with colorectal resection). The IMPRESS study provides a unique opportunity to assess the impact of the IQM peer review on the mortality in patients ventilated > 24 h. The secondary, exploratory, and qualitative analyses are expected to provide insights on determinants of in-hospital mortality, structure and process quality, and the robustness of different approaches to risk adjustment of quality indicators.

BackgroundAlthough clinical peer review is a well-established instrument for improving quality of care, clinical effectiveness is unclear.MethodsIn a pragmatic cluster randomised controlled trial, we randomly assigned 60 German Initiative Qualitätsmedizin member hospitals with the highest mortality rates in ventilated patients in 2016 to intervention and control groups. The primary outcome was hospital mortality rate in patients ventilated fore more than 24 hours. Clinical peer review was conducted in intervention group hospitals only. We assessed the impact of clinical peer review on mortality using a difference-in-difference approach by applying weighted least squares (WLS) regression to changes in age-adjusted and sex-adjusted standardised mortality ratios (SMRs) 1 year before and 1 year after treatment. Recommendations for improvement from clinical peer review and hospital survey data were used for impact and process analysis.ResultsWe analysed 12 058 and 13 016 patients ventilated fore more than 24 hours in the intervention and control hospitals within the 1-year observation period. In-hospital mortality rates and SMRs were 40.6% and 1.23 in intervention group and 41.9% and 1.28 in control group hospitals in the preintervention period, respectively. The groups showed similar hospital (bed size, ownership) and patient (age, sex, mortality, main indications) characteristics. WLS regression did not yield a significant difference between intervention and control groups regarding changes in SMRs (estimate=0.04, 95% CI= −0.05 to 0.13, p=0.38). Mortality remained high in both groups (intervention: 41.8%, control: 42.1%). Impact and process analysis indicated few perceived outcome improvements or implemented process improvements following the introduction of clinical peer review.ConclusionsThis study did not provide evidence for reductions in mortality in patients ventilated for more than 24 hours due to clinical peer review. A stronger focus on identification of structures and care processes related to mortality is required to improve the effectiveness of clinical peer review.

Background Postpancreatectomy haemorrhage (PPH) is a rare but potentially fatal complication after pancreatoduodenectomy. Preventive strategies are lacking with scarce data for support. The aim of this study was to investigate whether a prophylactic falciform ligament wrap around the hepatic and gastroduodenal artery can prevent PPH from these vessels. Methods In a randomized, controlled, multicentre trial, patients who were scheduled for elective open partial pancreatoduodenectomy with pancreatojejunostomy between 5 November 2015 and 2 April 2020 were randomly allocated in a 1 : 1 ratio to undergo pancreatoduodenectomy with (intervention) or without (control) a falciform ligament wrap around the hepatic artery. The primary endpoint was the rate of clinically relevant PPH from the hepatic artery or gastroduodenal artery stump within 3 months after pancreatoduodenectomy. Secondary endpoints were the rates of associated postoperative complications, for example postoperative pancreatic fistula (POPF) and PPH. Results Altogether, 445 patients were randomized with 222 and 223 in each group. Among the patients included in modified intention-to-treat analysis (207 in the intervention group and 210 in the control group), the primary endpoint was observed in six of 207 in the intervention group compared with 15 of 210 in the control group (2.9 versus 7.1 per cent respectively; odds ratio 0.39 (95 per cent c.i. 0.15 to 1.02); P = 0.071). Per protocol analysis showed a significant reduction in the intervention group (odds ratio 0.26 (95 per cent c.i. 0.09 to 0.80); P = 0.017). A soft pancreas texture (43 per cent) and the rate of a clinically relevant POPF were evenly (20 per cent) distributed between the groups. The rate of any clinically relevant PPH including the primary endpoint and other bleeding sites was not significantly different between intervention and control groups (9.7 versus 14.8 per cent respectively). Conclusion A falciform ligament wrap may reduce PPH from the hepatic artery or gastroduodenal artery stump and should be considered during pancreatoduodenectomy. Registration number: NCT02588066 (http://www.clinicaltrials.gov).

Background: Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality. Methods: We conducted a prospective study exploring the eight week time course of specific cellular (interferon-I³ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273. Results: SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% (p

SPIRIT 2013 checklist: recommended items to address in a clinical trial protocol and related documents. (DOC 127 kb)