CAR T-cell-associated secondary malignancies challenge current pharmacovigilance concepts.

Suspected adverse reactions following chimeric antigen receptor T-cell (CAR T) treatment include more and more cases of secondary T-cell malignancies. The causality assessment of such suspected reactions challenges established evaluation practices due to (i) patient and product-specific risk factors and (ii) incomplete data available with post-marketing reports submitted to competent authorities. This is of particular relevance for gene therapy products that integrate into the host genome.

A national surveillance system for continuous monitoring of blood transfusion safety: German haemovigilance data.

Background And Objectives: Haemovigilance (HV) systems aim to improve transfusion outcomes in patients and donor safety. An important question for blood regulators is how to ensure an effective HV system.

Materials And Methods: We retrospectively analysed the HV reports submitted to Paul-Ehrlich-Institut over the last two decades.

Regulatory Measures to Improve the Safety of CAR-T-Cell Treatment.

Introduction: Regulatory activities aim to facilitate the safe use of novel therapeutics such as genetically engineered chimeric antigen receptor (CAR)-T cells. Toxicities associated with CAR-T-cell therapies have led to modified safety management guidance in clinical trials and the implementation of post-marketing requirements. The aim of this study was to estimate the effect of individual risk-minimizing measures to evaluate the appropriateness of regulatory activities.

Analysis of Transfusion-Transmitted Bacterial Infections according to German Hemovigilance Data (2011-2020).

Introduction: Following the first assessment of the effects of safety measures taken against transfusion-transmitted bacterial infections (TTBI), the Paul-Ehrlich-Institut (PEI) decided to newly analyze risk minimization measures (RMM) using German hemovigilance data from 2011 to 2020, focusing on blood components, recipients, and bacterial strains.

Materials And Methods: The PEI assessed the imputability of all reported serious adverse reactions (SAR) relying mainly on microbiological test results. Reporting rates (RR) of suspected, confirmed, and fatal confirmed TTBI were calculated and compared to the previous reporting 10-year period (2001-2010) using Poisson regression to estimate RR ratios (RRR).

Monitoring Blood Supply in Germany: A Regulatory Perspective.

Background And Objectives: A sufficient supply of safe, high-quality blood components for transfusion is essential to the healthcare system in Germany. The requirements for the current reporting system are laid down in the German Transfusion Act. The present work elaborates on the advantages and limitations of the current reporting system and investigates the feasibility of a pilot project that collects specific data on blood supply based on weekly reports.

Follow-Up of Plasma Donors after Quarantine Storage: Results of a 5-Year Survey in Germany.

Background And Objectives: In 1993, a quarantine storage of 6 months was introduced for plasma for transfusion and was reduced to 4 months in 2003, owing to the improvements of screening assays used in German blood establishments. The presented survey analyses the value of quarantine storage under the current screening conditions.

Materials And Methods: From 2015 to 2019, we collected data on the total amount of released quarantine plasma as well as on the number of quarantine plasma not released due to a reactive screening test of a follow-up donation.

Blood Donation-Related Adverse Reactions: Results of an Online Survey among Donors in Germany (2018).

Introduction: According to German legislation, reports of suspected serious adverse reactions (AR) associated with the donation of blood and its components are continuously being evaluated by the Paul-Ehrlich-Institut. This survey aimed at providing a more complete picture of the AR associated with the donation of blood and blood components.

Materials And Methods: Eligible donors had the opportunity to anonymously report all AR occurring during or after their last donation by completing an online questionnaire.

Detectable SARS-CoV-2 RNAemia in Critically Ill Patients, but Not in Mild and Asymptomatic Infections.

Background: The SARS-CoV-2 pandemic has challenged many of our current routine practices in the treatment and care of patients. Given the critical importance of blood donation and transfusion we analyzed 92 blood samples of individuals infected with SARS-CoV-2 stratified by symptoms.

Study Design And Methods: We therefore tested blood samples for SARS-CoV-2 via RT-PCR targeting the E gene.

SARS-CoV-2 asymptomatic and symptomatic patients and risk for transfusion transmission.

Oral swabs, sputum, and blood samples from 18 asymptomatic and symptomatic patients with SARS-CoV-2 infection were examined using RT-PCR testing in order to assess the risk of transfusion-related transmission. In asymptomatic patients as well as patients with flu-like symptoms and fever, no SARS-CoV-2 RNA could be detected in the blood or serum despite a clearly positive result in all throat swabs. As patients with symptoms of infectious disease will not be admitted to blood donation, the risk for transfusion transmission of SARS-CoV-2 seems to be negligible.

Detection of hepatitis B virus infection in German blood donors 2008-2015.

Background And Objectives: Assessment of HBV-NAT testing compared to HBsAg and anti-HBc screening in German blood establishments for the period 2008-2015.

Materials And Methods: Blood donations screened for HBsAg and anti-HBc along with HBV-NAT were evaluated. Sensitivity of HBsAg and HBV-NAT tests was compared in 30 HBV seroconversion panels and with the viral load of the NAT-only cases.

Pathogen reduction of blood components during outbreaks of infectious diseases in the European Union: an expert opinion from the European Centre for Disease Prevention and Control consultation meeting.

Pathogen reduction (PR) of selected blood components is a technology that has been adopted in practice in various ways. Although they offer great advantages in improving the safety of the blood supply, these technologies have limitations which hinder their broader use, e.g.

Mortality, Morbidity and Related Outcomes Following Perioperative Blood Transfusion in Patients with Major Orthopaedic Surgery: A Systematic Review.

Background: Benefits and risks of liberal and restrictive transfusion regimens are under on-going controversial discussion. This systematic review aimed at assessing both regimens in terms of pre-defined outcomes with special focus on patients undergoing major orthopaedic surgery.

Methods: We performed a literature search for mortality, morbidity and related outcomes following peri-operative blood transfusion in patients with major orthopaedic surgery in electronic databases.

Impact of hepatitis E virus testing on the safety of blood components in Germany - results of a simulation study.

Hepatitis E virus (HEV) infections may be acquired through transfusion of blood components. As transfusion-transmitted infections mostly affect vulnerable individuals, measures to ensure the supply of safe blood components are under discussion. On the basis of the epidemiological situation in Germany, different testing strategy scenarios were investigated through simulation studies.

Evaluation of Risk Minimisation Measures for Blood Components - Based on Reporting Rates of Transfusion-Transmitted Reactions (1997-2013).

Background: To assess the impact of safety measures, we compared reporting rates of transfusion-related reactions before and after the implementation of six measures in 1999, 2004, 2006, 2008 and 2009.

Methods: Reporting rates of transfusion-transmitted bacterial infection (TTBI), viral infection (TTVI) and immune-mediated transfusion-related acute lung injury (TRALI) were calculated on the basis of confirmed annual reports and distributed blood components.

Results: The introduction of HCV NAT testing caused a significant reduction of HCV reporting rate from 1:0.

[Safety monitoring of cell-based medicinal products (CBMPs)].

Cell-based medicinal products (CBMPs), a category of advanced-therapy medicinal products (ATMPs), are authorised for the European market by the European Commission by means of the centralized marketing authorisation. By conforming to the German Medicinal Products Act (Sec. 4b AMG), national authorisation can be granted by the Paul-Ehrlich-Institut in Germany exclusively for ATMPs not based on a routine manufacturing procedure.

The role of isoagglutinins in intravenous immunoglobulin-related hemolysis.

Background: Increased reporting of intravenous immunoglobulin (IVIG)-related hemolytic reactions (HRs) triggered an investigation by the German and Swiss health authorities to identify potential risk factors.

Study Design And Methods: From the EudraVigilance database HRs reported between 2008 and 2013 were retrieved for seven IVIG preparations. HRs were classified as mild to moderate (hemoglobin [Hb] decline < 2 g/dL)] or severe (Hb decline > 2 g/dL) and separately analyzed for IVIG doses of less than 2 g/kg body weight and 2 g/kg body weight or more.

Risk Minimization Measures for Blood Screening HIV-1 Nucleic Acid Amplification Technique Assays in Germany.

Background: Several publications describe HIV-1 RNA false-negative results or viral load underquantitation associated with Communauté Européenne(CE)-marked qualitative or quantitative nucleic acid amplification technique (NAT) assays. 6 cases occurred during blood screening in Germany, with 2 of them causing HIV-1 transmissions to recipients of blood components. The implicated NAT assays were mono-target assays amplifying in different viral genome regions (gag or long terminal repeat).

Iron 10-thiacorroles: bioinspired iron(III) complexes with an intermediate spin (S=3/2) ground state.

A first systematic study upon the preparation and exploration of a series of iron 10-thiacorroles with simple halogenido (F, Cl, Br, I), pseudo-halogenido (N3 , I3 ) and solvent-derived axial ligands (DMSO, pyridine) is reported. The compounds were prepared from the free-base octaethyl-10-thiacorrole by iron insertion and subsequent ligand-exchange reactions. The small N4 cavity of the ring-contracted porphyrinoid results in an intermediate spin (i.

Sulfur-bridged BODIPY DYEmers.

Reactions of BODIPY monomers with sulfur nucleophiles and electrophiles result in the formation of new BODIPY dimers. Mono- and disulfur bridges are established, and the new dyestuff molecules were studied with respect to their structural, optical, and electrochemical properties. X-ray diffraction analyses reveal individual angulated orientations of the BODIPY subunits in all cases.

Transfusion-Transmitted Bacterial Infections - Haemovigilance Data of German Blood Establishments (1997-2010).

SUMMARY: METHODS: In order to evaluate the benefit of risk minimisation measures, reporting rates of transfusion-transmitted bacterial infections (TTBI) were calculated on the basis of annual reports and distributed blood components. Following the implementation of risk minimisation measures in 2003 and 2008, a comparison of pre- and post-implementation periods was performed. RESULTS: During a period of 14 years, 90 cases of TTBI were confirmed, 34 were caused by red blood cell (RBC) concentrates, 5 by fresh frozen plasma, and 51 by platelet concentrates (PCs).