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An international collaborative study was organised by the European Directorate for the Quality of Medicines & HealthCare (EDQM, Council of Europe) to calibrate replacement batches for the current European Pharmacopoeia (Ph. Eur.) Prekallikrein Activator (PKA) in albumin Biological Reference Preparation (BRP) whose stocks were dwindling. The study was run in the framework of the Biological Standardisation Programme (BSP) of the Council of Europe and the European Union (EU) Commission. Twenty-four laboratories from official medicines control authorities and manufacturers in Europe and outside Europe took part in the study. Three candidate replacement batches were produced with albumin solutions artificially spiked with a PKA concentrate to increase their PKA level. Participants were requested to evaluate the candidate batches against the 3rd World Health Organization (WHO) International Standard (IS) for Prekallikrein activator in albumin (16/364) using their routine assay method. The Ph. Eur. PKA in albumin BRP batch 7 (BRP7) was also included in the test panel to ensure the continuity of the consecutive BRP batches. The 3 candidate replacement batches were considered suitable for their intended use as BRPs. The study confirmed the stability of the PKA content of the current BRP7. Thermal stress study on the candidate batches confirmed the stability of their PKA activity. In December 2023, the Ph. Eur. Commission officially adopted the 3 candidate batches as Ph. Eur. PKA in albumin BRP batches 8, 9 and 10 with assigned potencies of 37 IU/vial, 33 IU/vial and 34 IU/vial, respectively. The activity of the 3 new batches of Ph. Eur. PKA in albumin BRP will be regularly monitored.

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Human immunoglobulin products are used for the treatment of a number of diseases, such as primary or secondary immunodeficiencies and autoimmune conditions due to the complete absence of antibodies or the production of defective immunoglobulins. Quality control of human immunoglobulin products is essential to ensure therapeutic functionality and safety. This includes testing for Fc function and anticomplementary activity (ACA), as well as verification of appropriate molecular size distribution using size-exclusion chromatography as prescribed in the European Pharmacopoeia (Ph. Eur.) monographs 0338, 0918, 2788 and 1928. To this end, specific biological reference preparations (BRPs) must be used. Stocks of the Ph. Eur. Human immunoglobulin (molecular size) BRP were running low and therefore a collaborative study was run by the European Directorate for the Quality of Medicines & HealthCare (EDQM), under the aegis of the Biological Standardisation Programme, to calibrate replacement batches. Eighteen laboratories, including manufacturers and Official Medicines Control Laboratories, took part in the study. Three batches of candidate BRPs were assessed and compared to Ph. Eur. Human immunoglobulin (molecular size) BRP 3 to ensure continuity. Based on the study results, the candidate BRPs were adopted by the Ph. Eur. Commission as Ph. Eur. Human immunoglobulin (molecular size) BRP batch 4, 5 and 6.

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A collaborative study was conducted to establish the first Indian Pharmacopoeia Reference Standard (IPRS) for teriparatide to be used in quality control testing of marketed products in compliance with the Indian Pharmacopoeia (IP) monograph. The study objective was to evaluate the candidate standard in terms of the WHO International Standard (IS) to assign its content in mg per vial terms. This study involved four laboratories from India and the candidate standard was calibrated against the WHO IS by each participant laboratory using high-performance liquid chromatography (HPLC) assay method per IP monograph. Direct calibration of the candidate standard resulted in an assigned content of 1.02 mg per vial. Based on the study results the candidate standard was judged suitable to serve as the first IPRS for teriparatide for identification and assay by HPLC.

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OBJECTIVE: Clinician-scientists are critical to medical innovation and research. However, the number of clinician scientists in the UK has been declining steadily over the last decade. One of the cited reasons is poor student recruitment to academic training pathways. The SMART study aims to assess current student perceptions on research and identify key factors influencing whether a student is interested in research. DESIGN: We conducted a cross-sectional survey study between January and May 2022. SETTING: This was a multi-centre national study with data collected across 40 universities offering medical courses in the UK. PARTICIPANTS: Participants were UK medical students enrolled in medicine for 21/22 academic year. MAIN OUTCOME AND MEASURE: The main outcomes were related to participant perceptions on research and whether they were interested in engaging with research in their future career. These measures were correlated with demographic and non-demographic details using regression analyses. RESULTS: One thousand seven hundred seventy-four individuals participated in the SMART survey from 40 medical schools. Nearly half the participants felt there were barriers preventing them from doing research (46.67%) and almost three-quarters felt it was at least somewhat difficult to combine research with medical school (73.49%). Of the options available, most commonly students did not want to pursue an academic career (43.11%) or training pathway (42.49%). However, most participants felt it was useful to do research at medical school (59.54%) and were also interested in doing more research in the future (69.16%). Regression analysis identified many factors influencing student's perceptions of research including year of study, gender, socioeconomic status, family background, research exposure at medical school, ethnicity, and country of pre-university education. CONCLUSIONS: The SMART study is the first of its kind in the UK, shedding light on medical student perceptions. While some express strong interest in academic careers, a larger proportion show a broader interest in research. Demographic factors like gender, parental occupation, and socioeconomic status play a role. Further exploration is needed for specific groups to address barriers, promote research, and boost academic pathway recruitment.

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The detection of hepatitis E virus (HEV) RNA is the gold standard for HEV infection diagnosis. In order to address the quality control requirements for HEV RNA detection kits within China, we aimed to establish the first Chinese national standard for HEV RNA detection through a collaborative study. The candidate standard was quantified using digital PCR (dPCR). A total of five laboratories were invited to determine the estimated mean value of this national standard relative to the World Health Organization International Standard (WHO IS). Additionally, four commercial kits were used to assess the applicability of the candidate standard. The stability was determined by freeze-thaw cycles and storage at 37 °C, 25 °C and 4 °C. The estimated mean value of this national standard relative to the WHO IS was 5.67 log10 IU/mL. Two out of the four commercial kits can detect as low as the estimated limit of detection (LOD). The degradation rates of samples in the stability study ranged from 4% to 19%. In conclusion, we have established the first Chinese national standard for HEV nucleic acid detection against WHO IS, which can be employed to evaluate the quality of HEV RNA detection kits.

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The viral genome titre is universally used for the dosing of adeno-associated virus (AAV)-based vectors used for gene therapy. To standardise this determination, the development of a common method would be valuable to facilitate comparison of viral doses used in the clinic and in the subsequent quality control of the products. A collaborative study was initiated by the Gene Therapy Working Group of the General European Official Medicines Control Laboratories Network in order to validate a qPCR-based method targeting the ITR2 sequence common to a broad variety of AAV vectors, independently from the serotype of the capsid or from the specific transgene. Five preparations of AAV vectors from various serotypes, including the AAV2/2 (RSS2) and AAV2/8 (RSS8) Reference Standard Stocks (American Type Culture Collection, USA) were used in the study. A plasmid carrying the ITR2 sequence was used to prepare standard curves. Its digestion outside the ITR regions facilitated melting of the hairpin ITR sequence during PCR, allowing better accessibility to the DNA polymerase. The results show that this qPCR method is satisfactory in terms of accuracy and precision. The reproducibility is also acceptable when compared with other similar studies, as it was shown previously that titres obtained by qPCR generally show higher inter-laboratory variability. The use of RSS2 or RSS8 as normalisation control in each assay demonstrated a promising help to identify potential sources of variation in a given laboratory or to smooth out inter-laboratory variations, thus improving reproducibility.

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BACKGROUND: Financial toxicity (FT) is a notable concern for patients with breast cancer worldwide. The situation regarding FT in Japan, however, has not been well explored. This study examined FT in patients with breast cancer in Japan and presented an overview of the group study's overall findings. METHODS: The survey used the Questant application and primarily targeted patients with breast cancer attending research facilities and physicians who are members of the Japanese Breast Cancer Society. The Japanese version of the Comprehensive Score for FT (COST) was used to quantify patients' FT. Multiple regression analysis was used to identify factors related to FT in patients with breast cancer in Japan and evaluate the sufficiency of information support level (ISL) for medical expenses. RESULTS: We collected 1558 responses from patients and 825 from physicians. In terms of factors affecting FT, recent payments had the highest impact, followed by stage, and related departments positively affecting FT. Conversely, factors such as income, age, and family support were found to negatively affect FT. A significant discrepancy was identified between patients and physicians in perceived information support, with patients frequently feeling unsupported and physicians believing that they have provided adequate support. Furthermore, differences in the frequency of explanations and opportunities to ask questions about medical costs across FT grades were found. The analysis also showed that physicians with a better understanding of information support needs and greater knowledge of medical costs tended to provide more support that is comprehensive. CONCLUSION: This study emphasizes the importance of addressing FT in patients with breast cancer in Japan and highlights the need for enhanced information support, deeper understanding by physicians, and collaborative efforts among professionals to mitigate financial burden and provide personalized, tailored support for individual needs.

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This study aimed to establish a second national standard for hepatitis B immunoglobulin (HBIG) that can be used for potency assays of hepatitis B and normal immunoglobulin. The candidate material was manufactured using a process approved as Good Manufacturing Practice. The freeze-dried candidate preparation was tested for physicochemical and biological properties, including pH, residual moisture, molecular size distribution, and potency. A collaborative study was performed involving four laboratories, including the National Institute of Food and Drug Safety Evaluation, as an official national control laboratory in Korea and manufacturers. The potency was calibrated against the second international standard for HBIG using two enzyme immunoassays: enzyme-linked immunosorbent assay and electrochemiluminescence immunoassay. Results from 240 assays were obtained from four laboratories, and combined potency estimates were obtained by calculating the geometric means. Intra- and inter-laboratory variability showed acceptable geometric coefficients of variation of 1.3-6.0 and 3.2-3.6%, respectively. The candidate preparation showed satisfactory stability in accelerated thermal degradation and real-time stability tests. Based on these results, the potency value of 105 IU/vial was assigned (95% confidence intervals: 100.0-109.2 IU/vial), and it was deemed suitable to serve as the Korean national standard for HBIG.

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Coxsackievirus A6 (CA6) is one of the major causative agents of herpangina and hand-foot-mouth disease (HFMD). Since 2008, CA6 has circulated widely around the world. Especially in Asia-Pacific region CA6 had even replaced enterovirus A71 (EV71) and coxsackievirus A16 (CA16) as the main prevalent strain of HFMD. In the recent 10 years, monovalent and multivalent vaccines against CA6 have been researched and developed by manufacturers from China, Korea, and the USA. The neutralizing antibody titer is a key indicator for accurately evaluating immunogenicity of vaccine. However, so far, the World Health Organization international standard for CA6 neutralizing antibody has not been available. In order to meet the needs of evaluating the immunogenicity of vaccines against CA6, the first Chinese national standard for CA6 neutralizing antibody was established, which was conducted to ensure that methods used to measure the neutralizing antibody titers against CA6 are accurate, reliable, and comparable. Three lyophilized candidate standards (29#, 39# and 44#) were produced with 0.40 ml/vial from plasma samples donated by healthy individuals. The collaborative study showed that the 29# candidate standard could effectively minimize the variability in neutralization titers between labs and across challenging viruses of different genotypes (A, D1, and D3). Therefore, the 29# candidate sample was established as the first Chinese national standard for CA6 neutralizing antibody test. This standard has good long-term stability and was assigned a potency of 150 units per milliliter (U/ml) of CA6 neutralizing antibody. It will contribute to ensure uniformity of potency or activity of vaccines and potentially therapeutic antibody preparations.

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Progress towards standardisation of allergen products has been made in recent years. Nevertheless, no standardised test method to quantify the allergen content of grass pollen allergen products is available at present. One aim of the BSP090 project was to validate a quantitative assay for a major Timothy grass (Phleum pratense) pollen allergen, Phl p 5. Qualification of a candidate ELISA system was performed with regard to range, robustness and cross-reactivity in preliminary studies. The assay specifically detected Phl p 5 with a quantification range from 3.9 ng/mL to 62.5 ng/mL. Suitability to quantify recombinant and natural Phl p 5 was further assessed in a collaborative study including 14 laboratories in Europe and the USA. Precision and accuracy of the assay was satisfactory with 93% of calculated Phl p 5 concentrations and 100% of total recoveries being within the ± 30% acceptance range. Similar results were obtained for spike recoveries, with exclusion of the lowest concentration spike, showing spike recoveries exceeding the acceptance range for six laboratories. Inter-assay (repeatability) and inter-laboratory (reproducibility) variability were satisfactory, in the format used in the present study. Robustness towards different statistical methods for data analysis was demonstrated. In conclusion, the assay can easily be established in routine testing and results of the preliminary testing and collaborative study support the proposal of the assessed Phl p 5-specific ELISA as a European Pharmacopoeia general method.

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Infant acute lymphoblastic leukemia (ALL), which develops in the first year of life, is a rare disease with approximately 20 cases per year in Japan. In particular, KMT2A (MLL) gene rearranged ALL (KMT2A-rALL) has a dismal prognosis, with a 5-year event-free survival rate of <50%. Moreover, acute and late severe toxicities from infants' intensive treatment remain an issue. Although outcomes of domestic and international clinical trials appear to improve gradually, the problem remains intractable. Therefore, introducing more appropriate risk stratification and less toxic and more effective novel treatment strategies is urgently required to improve the prognosis and long-term survival of infants with ALL. To achieve these goals, establishing new treatment strategies using novel agents through international collaborative studies is warranted in the future.

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A collaborative study for validating the determination method of chlorpropham in feeds by LC-MS/MS was conducted in 13 laboratories using 2 kinds of formula feeds, oats, barley, wheat, and corn. The resulting trueness ranged from 75.3 to 87.0%, repeatability and reproducibility in terms of relative standard deviation (RSDr and RSDR) were within 7.3% and 33% respectively, and the HorRat values ranged from 0.39 to 1.5. The limit of detection and limit of quantitation of chlorpropham in feed ware 0.008 mg/kg and 0.003 mg/kg, respectively. This method was thus validated as useful for inspections of chlorpropham in feed.

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Due to the diminished stocks of the third batch of the European Pharmacopoeia (Ph. Eur.) Biological Reference Preparation (BRP) for Human immunoglobulin for electrophoresis, in 2020 the European Directorate for the Quality of Medicines & HealthCare (EDQM) initiated an international collaborative study for the establishment of a replacement batch. The study was run under the aegis of the Biological Standardisation Programme (BSP). Nineteen laboratories participated in the collaborative study to verify the suitability of the candidate reference preparations according to the Ph. Eur. monographs Human normal immunoglobulin for intravenous administration (0918), Human normal immunoglobulin for intramuscular administration (0338) and Human normal immunoglobulin for subcutaneous administration (2788) using the zone electrophoresis method with cellulose acetate and/or agarose as the testing medium. Capillary zone electrophoresis (CZE), a technique not yet included in monographs 0338, 0918 and 2788, was also used by some laboratories. The assignment of a value for immunoglobulin as a percentage of the total protein content could only be made for agarose electrophoresis and for CZE. The candidate preparation was found suitable for the intended purpose and was subsequently adopted by correspondence in May 2021 by the Ph. Eur. Commission as Human immunoglobulin for electrophoresis BRP batch 4 with an assigned range for immunoglobulin of 82.5 % to 87.8 % of the total protein content.

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Reliable and accurate quantification of cell-associated HIV DNA (CA HIV DNA) is critical for early infant diagnosis, clinical management of patients under therapy, and to inform new therapeutics efficacy. The present study assessed the variability of CA HIV DNA quantification obtained from various assays and the value of using reference materials to help harmonize the measurements. Using a common set of reagents, our multicenter collaborative study highlights significant variability of CA HIV DNA quantification and lower limit of quantification across assays. The quantification of CA HIV DNA from a panel of infected PBMCs can be harmonized through cross-subtype normalization but assay calibration with the commonly used 8E5 cell line failed to reduce quantification variability between assays, demonstrating the requirement to thoroughly evaluate reference material candidates to help improve the comparability of CA HIV DNA diagnostic assay performance. IMPORTANCE Despite a global effort, HIV remains a major public health burden with an estimated 1.5 million new infections occurring in 2020. HIV DNA is an important viral marker, and its monitoring plays a critical role in the fight against HIV: supporting diagnosis in infants and underpinning clinical management of patients under therapy. Our study demonstrates that HIV DNA measurement of the same samples can vary significantly from one laboratory to another, due to heterogeneity in the assay, protocol, and reagents used. We show that when carefully selected, reference materials can reduce measurement variability and harmonize HIV DNA quantification across laboratories, which will help contribute to improved diagnosis and clinical management of patients living with HIV.

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Background: The forecast accuracy of the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) and Asian Pacific Association for the Study of the Liver (APASL) acute-on-chronic liver failure (ACLF) criteria in assessing long-term outcomes after liver transplantation (LT) is still unclear, especially when the staging of the two standards is inconsistent. Methods: A retrospective cohort (NCT05036031) including 565 patients from January 2015 to June 2021 was conducted. The 28 and 90 days, 1- and 3-years overall survival (OS) after LT were compared between different grades. Findings: Total of 162 (28.7%) and 230 (40.7%) patients met the ACLF standards. In the EASL-CLIF criteria, the 3-year OS rates were 83·0%, 80·3%, and 69·8% for ACLF1-3, respectively. In the APASL criteria, the 3-year OS rates were 85·7% for APASL ACLF Research Consortium (AARC)-1, similar to ACLF-1. The 3-year OS rates were 84·5% for AARC-2, which were slightly better than ACLF-2. Regarding AARC-3, the 3-year OS rate was 5·8% higher than ACLF-3. For patients who met neither set of criteria for ACLF, the 3-year OS rates were 89·8%. The multivariate analysis showed that alanine aminotransferase >100 U/L, respiration failure, and cerebral failure were independent risk factors for post-LT death. Interpretation: This study provides the first large-scale long-term follow-up data in Asia. Both criteria showed favorable distinguishing ability for post-LT survival. Patients with ACLF had a higher post-LT mortality risk, and ACLF-3 and AARC-3 correlated with significantly greater mortality. Funding: National Natural Science Foundation of China and Science and Technology Commission of Shanghai Municipality.

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The study of clinical high risk for psychosis (CHR-P) has progressed rapidly over the last decades and has developed into a significant branch of schizophrenia research. Organizing the information about this rapidly growing subject through bibliometric analysis enables us to gain a better understanding of current research trends and future directions to be pursued. Electronic searches from January 1991 to December 2020 yielded 5,601 studies, and included 1,637 original articles. After processing the data, we were able to determine that this field has grown significantly in a short period of time. It has been confirmed that researchers, institutions, and countries are collaborating closely to conduct research; moreover, these networks are becoming increasingly complex over time. Additionally, there was a shift over time in the focus of the research subject from the prodrome, recognition, prevention, diagnosis to cognition, neuroimaging, neurotransmitters, cannabis, and stigma. We should aim for collaborative studies in which various countries participate, thus covering a wider range of races and cultures than would be covered by only a few countries.

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Human immunoglobulin products are used for the treatment of a number of diseases, such as primary or secondary immunodeficiencies and autoimmune conditions due to the complete absence of antibodies or the production of defective immunoglobulins. Quality control of human immunoglobulin products is essential to ensure therapeutic functionality and safety. This includes testing for Fc function and anticomplementary activity (ACA), as well as verification of appropriate molecular size distribution using size-exclusion chromatography as prescribed in the European Pharmacopoeia (Ph. Eur.) monographs 0338, 0918, 2788 and 1928. To this end, specific biological reference preparations (BRPs) must be used. Stocks of the Ph. Eur. Human immunoglobulin for anticomplementary activity BRP were running low and therefore a collaborative study was run by the European Directorate for the Quality of Medicines & HealthCare (EDQM), under the aegis of the Biological Standardisation Programme, to calibrate replacement batches. Six laboratories, including manufacturers and one Official Medicines Control Laboratory, took part in the study. Several batches of candidate BRPs were calibrated against Ph. Eur. Human immunoglobulin for anticomplementary activity BRP batch 2 to ensure continuity. Based on the study results, the candidate BRPs were adopted by the Ph. Eur. Commission as Ph. Eur. human immunoglobulin for anticomplementary activity BRP batch 3, 4, 5 and 6.

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To comply with European Pharmacopoeia (Ph. Eur.) monograph Human albumin solution (0255), albumin solutions have to be tested for molecular-size distribution by size-exclusion chromatography (SEC). However, differences in interpretation of the test results continue to be observed among albumin manufacturers in Europe. A collaborative study was run by the European Directorate for the Quality of Medicines & HealthCare (EDQM), under the aegis of the Biological Standardisation Programme (BSP), to support the revision of Ph. Eur. monograph 0255 and to establish a Biological Reference Preparation (BRP) for use in the molecular-size distribution test. In 2019, Ph. Eur. Expert Group 6B proposed to include an analytical improvement of the SEC procedure in the monograph, which was then submitted for public enquiry. This publication describes the evaluation of three candidate BRPs to serve as a tool for both the system suitability test (SST) and albumin monomer and dimer peak identification according to the proposed revised methodology. Three Official Medicines Control Laboratories (OMCLs) involved in the official batch release of human albumin solution took part in the study. Based on the study results, the candidate BRPs were found suitable for purpose and were adopted by the Ph. Eur. Commission as Ph. Eur. Human albumin (molecular size) BRP batches 1, 2 and 3 concomitantly with the revised monograph Human albumin solution (0255) in November 2020.

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Acute lymphoblastic leukemia (ALL) in infants, especially KMT2A gene rearranged ALL (KMT2A-rALL), is a rare disease. Its prognosis is extremely poor, with a reported long-term event-free survival rate of ≤50%. In addition, acute and late toxicities caused by intensive treatment remain issues to be resolved. In the context of this background, the introduction of a more appropriate stratification and a novel treatment with minimal toxicities are urgently required. Establishment of evidence-based novel treatment strategies through an international collaborative study is important owing to the rarity of the disease. Currently, an international collaborative study with a European study group, which includes blinatumomab combined therapy, has been proposed. We herein review previous key clinical trials and the latest treatment strategies for infant ALL.

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We have developed a quantitative determination method of the concentration of inorganic arsenic in pet foods using a liquid chromatograph-inductively coupled plasma-mass spectrometer (LC-ICP-MS). After adding 2 w/v% TMAH solution to a sample, inorganic arsenic was extracted by heating and the extract was collected by water. The pH of the solution was adjusted, and injected into a LC-ICP-MS to determine the concentration of inorganic arsenic. LC separation was carried out on an ODS column with 10 mmol/L sodium 1-butanesulfonate, 4 mmol/L malonic acid, 4 mmol/L TMAH and 0.05% methanol solution as a mobile phase. A collaborative study was conducted by nine laboratories using dry and wet-type pet foods, formed jerky, dried jerky and biscuit. Dry-type pet food and dried jerky was added with 2 mg/kg of As (III). Wet-type pet food was added with 0.5 mg/kg of As (III). Formed jerky was added with 1 mg/kg of As (III). Biscuit was added with 0.2 mg/kg of As (III). The mean recoveries, repeatabilities and reproducibilities in the form of relative standard deviation (RSDr and RSDR), and HorRat, were 95.4% to 98.3%, less than 2.9%, less than 9.1%, and 0.22 to 0.51, respectively.

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