Inconsistency in ferritin reference intervals across laboratories: a major concern for clinical decision making.

OBJECTIVES: Iron deficiency anemia is a significant global health concern, diagnosed by measuring hemoglobin concentrations in combination with plasma ferritin concentration. This study investigated the variability in ferritin reference intervals among laboratories in the Netherlands and examined how this affects the identification of iron-related disorders. METHODS: Ferritin reference intervals from 52 Dutch ISO15189-certified medical laboratories were collected. Ferritin, hemoglobin and mean corpuscular volume data of non-anemic apparently healthy primary care patients, measured by four laboratory platforms (Beckman, Abbott, Siemens, and Roche), were collected (n=397,548). Median ferritin levels were determined per platform, stratified by sex and age. The proportion of ferritin measurements outside of the reference interval was calculated using the reference intervals from the 52 laboratories (using a total of n=1,093,442 ferritin measurements). Lastly, ferritin data from 3,699 patients as captured in general practitioner (GP) data from the PHARMO Data Network were used to assess the variation of abnormal ferritin measurements per GP. RESULTS: Median plasma ferritin concentrations were approximately four times higher in men and twice as high in postmenopausal women compared to premenopausal women. Moreover, there are substantial differences in the median plasma ferritin concentration between the four platforms. However, even among laboratories using the same platform, ferritin reference intervals differ widely. This leads to significant differences in the percentages of measurements classified as abnormal, with the percentage of ferritin measurements below the reference limit in premenopausal women ranging from 11 to 53 %, in postmenopausal women from 3 to 37 %, and in men from 2 to 19 %. The percentage of ferritin measurements above the reference limit in premenopausal women ranged from 0.2 to 11 %, in postmenopausal women from 3 to 36 % and in men from 7 to 32 %. CONCLUSIONS: The lack of harmonization in ferritin measurement and the disagreement in plasma ferritin reference intervals significantly impact the interpretation of the iron status of patients and thereby the number of iron disorder diagnoses made. Standardization or harmonization of the ferritin assays and establishing uniform reference intervals and medical decision limits are essential to reduce the substantial variability in clinical interpretations of ferritin results.

Evaluation of the review models and approval timelines of authorities participating in the East African Medicine Regulatory Harmonisation initiative: alignment and strategies for moving forward.

Introduction: Medicines regulatory harmonisation has been embraced by many national regulatory authorities (NRAs) to improve public health through faster availability of safe, high-quality, and effective medical products to patients and enhanced standardisation of technical guidelines and work sharing, leading to reduced cost to pharmaceutical companies. After ten years of implementing regulatory harmonisation by the East African Community Medicines Registration Harmonization (EAC-MRH) initiative, it is now imperative for participating NRAs to rely on each other to minimise duplication of use of limited resources. Major challenges in implementing reliance are the lack of clear registration processes and delays in the approval. The aim of this study was to compare review models, target timelines and data requirements used in assessing applications by EAC-MRH NRAs so as to align and propose strategies for improvement. Methods: A validated questionnaire that standardises and captures review processes was completed by the head of the medicine's registration division in each of the seven EAC-MRH NRAs. A country report based on the completed questionnaire was developed for each NRA and validated by the heads of the respective authorities. Results: Most applications received by all countries were for generics except Kenya, which received a significant number of new active substance applications (55 and 53 in 2020 and 2021). Mean approval times for generics using full review varied, with Tanzania's time declining for the three years. Target timelines for full review for the five countries ranged between 180 calendar days (Tanzania) to the highest 330 days (Zanzibar). The three countries (Kenya, Rwanda and Uganda) utilising the verification review model had a target timeline of 90 days. All six authorities conducted abridged reviews and fast-track assessments through a priority review track. The common technical document format was mandatory for applications in all authorities. The target timeline for key milestones in the review process varied for each country with a few similarities. Discussion: The study has provided a baseline for review models, target timelines and data requirements utilised in assessing applications for registration by EAC-MRH NRAs. Implementing the recommendations from this study will enable the NRAs to align and improve their registration processes.

Blood Harmonisation of Endoscopic Transsphenoidal Surgical Video Frames on Phantom Models.

Physical phantom models have been integral to surgical training, yet they lack realism and are unable to replicate the presence of blood resulting from surgical actions. Existing domain transfer methods aim to enhance realism, but none facilitate blood simulation. This study investigates the overlay of blood on images acquired during endoscopic transsphenoidal pituitary surgery on phantom models. The process involves employing manual techniques using the GIMP image manipulation application and automated methods using pythons Blend Modes module. We then approach this as an image harmonisation task to assess its practicality and feasibility. Our evaluation uses Structural Similarity Index Measure and Laplacian metrics. The results we obtained emphasize the significance of image harmonisation, offering substantial insights within the surgical field. Our work is a step towards investigating data-driven models that can simulate blood for increased realism during surgical training on phantom models.

Measuring bile acids: Are we all talking the same language?

In this paper, we discuss the Bile Acid Comparison and Harmonisation project, a sub-study of the Trial of URsodeoxycholic acid vs RIFampicin in early-onset severe Intrahepatic Cholestasis of pregnancy, giving an overview of the current state of affairs for total bile acid measurements.

Evaluation of good review practices in member authorities of the East African Medicines Regulatory Harmonisation initiative: strategies for alignment with African medicines agency.

Introduction: The East African Community Medicines Regulatory Harmonisation (EAC-MRH) programme was established to address challenges faced by national regulatory authorities (NRAs) of the region. Work sharing through joint assessments and inspections was adopted to manage limited resources and capacity; however, NRA good review practices (GrevP) are also a key determinant to success. This study evaluated GReVP among the EAC-MRH NRAs and mapped required strategies for countries to align themselves with the African Medicines Agency (AMA). Methods: A validated questionnaire (Optimising Efficiency in Regulatory Agency-OpERA) that standardises and captures review processes was completed by the head of the medicines registration division in each NRA. A country report based on the completed questionnaire was developed for each NRA and validated by the heads of the respective authorities. Results: The population and size of the NRAs vary and four of the countries have semi-autonomous authorities and three NRAs are autonomous. The Burundi and South Sudan authorities were fully government funded, Kenya and Uganda entirely from fees, while Rwanda, Tanzania and Zanzibar were partially funded from different sources. All authorities except South Sudan, which does not receive or review applications had backlogs. Authority fees varied based on the different application categories. Key milestones for standardised regulatory processes are implemented in all authorities. Queue times range from a few weeks to about one year. Three NRAs use internal technical agency staff for scientific assessments and three use both internal and external experts. Clock stop time varies and target timelines for review committee range from one day to three months. All the NRAs implement some best practices on quality measures, transparency and communication. Some have activities for transparency improvement but with minimal attention to training and education. Most employ some quality decision-making practices. Discussion: GrevP in EAC-MRH NRAs still needs to be improved and it is imperative that these authorities streamline and harmonise their practices. Increasing human resources and an investment in training and education of staff will enable the implementation of all measures for GRevP. This is vital, as the effectiveness and efficiency of the AMA will depend on the strength of these NRAs.

Comparison of PD-L1 assays in head and neck carcinoma.

Programmed cell death-ligand 1 (PD-L1) expression is a predictive biomarker for response to immune checkpoint inhibitor in head and neck squamous cell carcinoma. Given the range of antibodies and platforms for PD-L1 testing, it is essential to understand the performance of different staining and scoring methods. PD-L1 expression in 156 head and neck mucosal squamous cell carcinoma (HNmSCC) cases at Asan Medical Center was assessed using 106 tissue microarray (TMA) cores and 50 whole slides. Three standardised PD-L1 assays (22C3 pharmDx, SP263, and 28-8 pharmDx) and one laboratory-developed test (22C3 LDT) were evaluated: the combined positive score (CPS) with ≥1, ≥20, and ≥50 cut-offs, and the tumour positive score (TPS) with ≥1%, ≥20%, ≥50% cut-offs. Concordance on a continuous scale among the assays was good to excellent for CPS [intraclass correlation coefficient (ICC) range 0.73-0.94] and TPS (ICC range 0.70-0.94) and in both TMA and whole slides cohorts. Stratification by variable cut-offs demonstrated moderate to good agreement among most assays, as analysed by Gwet's AC1. PD-L1 expression was significantly correlated with tumour location using the 22C3 pharmDx assay (CPS, p=0.014; TPS, p=0.033). Notable concordance was found among PD-L1 assays, suggesting their potential interchangeability in HNmSCC.

Comparison of Three Regional Medicines Regulatory Harmonisation Initiatives in Africa: Opportunities for Improvement and Alignment.

BACKGROUND: The African Medicines Regulatory Harmonisation (AMRH) Initiative was formed in 2009 and subsequently, three regional initiatives (East African Community Medicines Regulatory Harmonisation [MRH], Southern African Development Community [SADC]/ZaZiBoNa MRH, and the Economic Community of West Africa States MRH) were established. As these initiatives serve as a foundation for the African Medicines Agency (AMA), the aim of this study was to compare their operating models, successes and challenges to identify opportunities for improvement and alignment. METHODS: A mixed method approach was used for the data collection using a questionnaire, the Process, Effectiveness and Efficiency Rating (PEER), developed by the authors specifically for this study and semi-structured interview techniques. There were 23 study participants (one from each agency of the member countries of the three regions). It was hoped that data generated from this study would lead to a series of recommendations, which would then be ratified by the regulatory authorities. RESULTS: Most respondents stated that AMRH contributed to the strengthening of regulatory systems and harmonising regulatory requirements across economic regions of Africa, potentially resulting in improved access to quality-assured medicines. Although established at different times and at the discretion of each region, the marketing authorisation application review processes are largely similar, with a few differences noted in the eligibility and submission requirements, type of procedures employed, the timelines and fees payable. The challenges identified in the three regions are also similar, with the most noteworthy being the lack of a binding legal framework for regional approvals. CONCLUSION: In this study, we compared the process, successes and challenges of these three regional harmonisation initiatives in Africa addressing the areas of legal frameworks, information management systems, the accessibility and affordability of medicines and reliance that will bring greater alignment and efficiency in their operating models, thereby strengthening the foundation of the soon-to-be-operationalised AMA.

Facing further challenges in cancer data quality and harmonisation.

This article highlights the recent and ongoing activities of European population-based cancer registries (PBCRs) in data quality and harmonisation in the framework of the collaboration between the European Network of Cancer Registries (ENCR) and the Directorate-General Joint Research Centre (JRC), the science and knowledge centre of the European Commission. The article concludes the Frontiers in Oncology's Research Topic "Joining Efforts to Improve Data Quality and Harmonization Among European Population-Based Cancer Registries", which has been an opportunity for several European researchers to share their experience on cancer data quality and harmonisation. Such experience will be helpful for PBCRs in view of future challenges and opportunities in cancer epidemiology, with a few examples discussed in the present article.

Data and Process Harmonisation of Multi-National, Multi-Site Research Data.

To achieve a single fully harmonised research data set suitable for analysis from data collected at multiple sites requires not only semantic integration of collection concepts and convergence onto single collection units, but harmonisation of data collection processes. We describe our experience of identifying harmonisation challenges in the Precision ALS project, with particular focus on process alignment challenges in a multi-site multi-national research data collection project.

Floating microplastics in Svalbard fjords: High spatial variability requires methodological consistency in estuarine systems.

Microplastic pollution was studied in surface waters of Isfjorden, Svalbard in July 2021 as a part of an international regional harmonisation exercise. Surface microplastics (0.5-5 mm) were sampled with a neuston net in triplicate per study site in several branches of Isfjorden, covering populated and unpopulated fjords. High spatial variability of microplastic abundance (0-32,700 items/km2) was observed within a single fjord resulting from the hydrodynamic pattern formed through the interaction of surface currents, freshwater runoff, and wind conditions. Maximum microplastic abundance was not correlated with the distance from the local source and was instead defined by local small-scale hydrodynamics. Future recommendations for correct assessment of surface microplastics concentration in estuarine environments are presented.

Using natural language processing to facilitate the harmonisation of mental health questionnaires: a validation study using real-world data.

BACKGROUND: Pooling data from different sources will advance mental health research by providing larger sample sizes and allowing cross-study comparisons; however, the heterogeneity in how variables are measured across studies poses a challenge to this process. METHODS: This study explored the potential of using natural language processing (NLP) to harmonise different mental health questionnaires by matching individual questions based on their semantic content. Using the Sentence-BERT model, we calculated the semantic similarity (cosine index) between 741 pairs of questions from five questionnaires. Drawing on data from a representative UK sample of adults (N = 2,058), we calculated a Spearman rank correlation for each of the same pairs of items, and then estimated the correlation between the cosine values and Spearman coefficients. We also used network analysis to explore the model's ability to uncover structures within the data and metadata. RESULTS: We found a moderate overall correlation (r = .48, p < .001) between the two indices. In a holdout sample, the cosine scores predicted the real-world correlations with a small degree of error (MAE = 0.05, MedAE = 0.04, RMSE = 0.064) suggesting the utility of NLP in identifying similar items for cross-study data pooling. Our NLP model could detect more complex patterns in our data, however it required manual rules to decide which edges to include in the network. CONCLUSIONS: This research shows that it is possible to quantify the semantic similarity between pairs of questionnaire items from their meta-data, and these similarity indices correlate with how participants would answer the same two items. This highlights the potential of NLP to facilitate cross-study data pooling in mental health research. Nevertheless, researchers are cautioned to verify the psychometric equivalence of matched items.

Immune-related adverse events of antibody-based biological medicines in cancer therapy.

Recombinant antibodies (Abs) are an integral modality for the treatment of multiple tumour malignancies. Since the Food and Drug Administration (FDA) approval of rituximab as the first monoclonal antibody (mAb) for cancer treatment, several mAbs and antibody (Ab)-based therapies have been approved for the treatment of solid tumour malignancies and other cancers. These Abs function by either blocking oncogenic pathways or angiogenesis, modulating immune response, or by delivering a conjugated drug. The use of Ab-based therapy in cancer patients who could benefit from the treatment, however, is still limited by associated toxicity profiles which may stem from biological features and processes related to target binding, alongside biochemical and/or biophysical characteristics of the therapeutic Ab. A significant immune-related adverse event (irAE) associated with Ab-based therapies is cytokine release syndrome (CRS), characterized by the development of fever, rash and even marked, life-threatening hypotension, and acute inflammation with secondary to systemic uncontrolled increase in a range of pro-inflammatory cytokines. Here, we review irAEs associated with specific classes of approved, Ab-based novel cancer immunotherapeutics, namely immune checkpoint (IC)-targeting Abs, bispecific Abs (BsAbs) and Ab-drug-conjugates (ADCs), highlighting the significance of harmonization in preclinical assay development for safety assessment of Ab-based biotherapeutics as an approach to support and refine clinical translation.

C-Reactive Protein and Brain Natriuretic Peptides Harmonization.

The harmonization of laboratory biomarkers is pivotal in ensuring consistent and reliable diagnostic outcomes across different clinical settings. This systematic review examines the harmonization of C-Reactive Protein (CRP) and N-Terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) measurements, both of which are jointly utilized in the diagnosis and management of cardiovascular diseases. To identify relevant studies, we searched the PubMed electronic database using specific medical subject headings and keywords such as C-Reactive Protein, CRP, high sensitivity C-Reactive Protein (hs-CRP), N-terminal pro B-type natriuretic peptide, and NT-proBNP, focusing on publications from June 1 to September 26, 2021. The query filtered studies to include only those in English involving human subjects. From our search, 97 articles met the inclusion criteria and were included for in-depth analysis. Despite their widespread use, significant variability remains in the measurements of CRP and NT-proBNP due to a lack of standardized pre-analytical, analytical, and post-analytical practices. This review highlights the consequences of this variability on clinical decision-making and patient outcomes and emphasizes the need for international standards and guidelines to achieve better harmonization. Our findings advocate for the establishment of universal protocols to enhance the reliability of these biomarker measurements across different clinical environments, ensuring improved healthcare delivery.

A comparative study of medical device regulation between countries based on their economies.

INTRODUCTION: Medical devices play a crucial role in healthcare, addressing the diagnosis, treatment, and monitoring of various medical conditions. This study conducts a comprehensive analysis of medical device regulations across nations, considering the economic contexts of diverse countries. AREAS COVERED: The research involves a comparative examination of medical device regulations, dissecting unique frameworks in countries like the United States (US), European Union (EU), India, and Africa. These nations were chosen based on economic significance, market influence, and regulatory structures. The study aims to achieve a nuanced understanding of global medical device regulation, develop strategies to enhance guidelines, especially in developing nations, and provide recommendations for improvements in relevant regions. EXPERT OPINION: Through this study, valuable insights are gained into the diverse regulatory frameworks governing medical devices globally. The analysis identifies areas within these frameworks that require improvement, as well as strategies to enhance regulatory guidelines, particularly addressing the specific needs of developing economies. Ultimately, the research provides significant recommendations for policymakers and industry stakeholders. By offering a deeper understanding of regulatory intricacies, this study establishes pragmatic approaches to address challenges within the medical device industry and improve the regulatory landscape on a global scale.

Transforming a Large-Scale Prostate Cancer Outcomes Dataset to the OMOP Common Data Model-Experiences from a Scientific Data Holder's Perspective.

To enhance international and joint research collaborations in prostate cancer research, data from different sources should use a common data model (CDM) that enables researchers to share their analysis scripts and merge results. The OMOP CDM maintained by OHDSI is such a data model developed for a federated data analysis with partners from different institutions that want to jointly investigate research questions using clinical care data. The German Cancer Society as the scientific lead of the Prostate Cancer Outcomes (PCO) study gathers data from prostate cancer care including routine oncological care data and survey data (incl. patient-reported outcomes) and uses a common data specification (called OncoBox Research Prostate) for this purpose. To further enhance research collaborations outside the PCO study, the purpose of this article is to describe the process of transferring the PCO study data to the internationally well-established OMOP CDM. This process was carried out together with an IT company that specialised in supporting research institutions to transfer their data to OMOP CDM. Of n = 49,692 prostate cancer cases with 318 data fields each, n = 392 had to be excluded during the OMOPing process, and n = 247 of the data fields could be mapped to OMOP CDM. The resulting PostgreSQL database with OMOPed PCO study data is now ready to use within larger research collaborations such as the EU-funded EHDEN and OPTIMA consortium.

Recommendations for data collection in cohort studies of preterm born individuals - The RECAP Preterm Core Dataset.

BACKGROUND: Preterm birth (before 37 completed weeks of gestation) is associated with an increased risk of adverse health and developmental outcomes relative to birth at term. Existing guidelines for data collection in cohort studies of individuals born preterm are either limited in scope, have not been developed using formal consensus methodology, or did not involve a range of stakeholders in their development. Recommendations meeting these criteria would facilitate data pooling and harmonisation across studies. OBJECTIVES: To develop a Core Dataset for use in longitudinal cohort studies of individuals born preterm. METHODS: This work was carried out as part of the RECAP Preterm project. A systematic review of variables included in existing core outcome sets was combined with a scoping exercise conducted with experts on preterm birth. The results were used to generate a draft core dataset. A modified Delphi process was implemented using two stages with three rounds each. Three stakeholder groups participated: RECAP Preterm project partners; external experts in the field; people with lived experience of preterm birth. The Delphi used a 9-point Likert scale. Higher values indicated greater importance for inclusion. Participants also suggested additional variables they considered important for inclusion which were voted on in later rounds. RESULTS: An initial list of 140 data items was generated. Ninety-six participants across 22 countries participated in the Delphi, of which 29% were individuals with lived experience of preterm birth. Consensus was reached on 160 data items covering Antenatal and Birth Information, Neonatal Care, Mortality, Administrative Information, Organisational Level Information, Socio-economic and Demographic information, Physical Health, Education and Learning, Neurodevelopmental Outcomes, Social, Lifestyle and Leisure, Healthcare Utilisation and Quality of Life. CONCLUSIONS: This core dataset includes 160 data items covering antenatal care through outcomes in adulthood. Its use will guide data collection in new studies and facilitate pooling and harmonisation of existing data internationally.

Comparison of permitted daily exposure (PDE) values for active pharmaceutical ingredients (APIs) - Evidence of a robust approach.

Permitted Daily Exposure Limits (PDEs) are set for Active Pharmaceutical Ingredients (APIs) to control cross-contamination when manufacturing medicinal products in shared facilities. With the lack of official PDE lists for pharmaceuticals, PDEs have to be set by each company separately. Although general rules and guidelines for the setting of PDEs exist, inter-company variations in the setting of PDEs occur and are considered acceptable within a certain range. To evaluate the robustness of the PDE approach between different pharmaceutical companies, data on PDE setting of five marketed APIs (amlodipine, hydrochlorothiazide, metformin, morphine, and omeprazole) were collected and compared. Findings show that the variability between PDE values is within acceptable ranges (below 10-fold) for all compounds, with the highest difference for morphine due to different Point of Departures (PODs) and Adjustment Factors (AFs). Factors of PDE variability identified and further discussed are: (1) availability of data, (2) selection of POD, (3) assignment of AFs, (4) route-to-route extrapolation, and (5) expert judgement and differences in company policies. We conclude that the investigated PDE methods and calculations are robust and scientifically defensible. Additionally, we provide further recommendations to harmonize PDE calculation approaches across the pharmaceutical industry.

A Harmonised Approach to Curating Research-Ready Datasets for Asthma, Chronic Obstructive Pulmonary Disease (COPD) and Interstitial Lung Disease (ILD) in England, Wales and Scotland Using Clinical Practice Research Datalink (CPRD), Secure Anonymised Information Linkage (SAIL) Databank and DataLoch.

Background: Electronic healthcare records (EHRs) are an important resource for health research that can be used to improve patient outcomes in chronic respiratory diseases. However, consistent approaches in the analysis of these datasets are needed for coherent messaging, and when undertaking comparative studies across different populations. Methods and Results: We developed a harmonised curation approach to generate comparable patient cohorts for asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) using datasets from within Clinical Practice Research Datalink (CPRD; for England), Secure Anonymised Information Linkage (SAIL; for Wales) and DataLoch (for Scotland) by defining commonly derived variables consistently between the datasets. By working in parallel on the curation methodology used for CPRD, SAIL and DataLoch for asthma, COPD and ILD, we were able to highlight key differences in coding and recording between the databases and identify solutions to enable valid comparisons. Conclusion: Codelists and metadata generated have been made available to help re-create the asthma, COPD and ILD cohorts in CPRD, SAIL and DataLoch for different time periods, and provide a starting point for the curation of respiratory datasets in other EHR databases, expediting further comparable respiratory research.

Limitations of current analytical reference methods to determine vitamins in foods: Challenges to support regulatory compliance and nutritional composition data.

Foods are analysed for their vitamin content to support the verification of regulatory compliance or to generate food composition data. Many international reference methods for the analysis of vitamins in foods originate from the 1990s. Advances in nutrition science and analytical technology and the continuing evolution of statutory regulations necessitate the need of new or supplementary regulatory standards. We have evaluated recent developments in these areas and conclude that most current international reference methods are no longer fit-for-purpose to accurately determine vitamin content in foods and food supplements. We have made recommendations to consider new and/or updated reference methods and regulatory standards for the analysis of vitamins A, D, E, K, B1, B2, B3, B5, B6, B7, B9, B12, C and carotenoids in foods and food supplements. This area of nutrients may benefit from globally harmonised definitions specifying what compounds to include or exclude for analysis, and applicable bioactivity factors.

Essential data variables for a minimum dataset for head and neck cancer trials and clinical research: HNCIG consensus recommendations and database.

The Head and Neck Cancer International Group (HNCIG) has undertaken an international modified Delphi process to reach consensus on the essential data variables to be included in a minimum database for HNC research. Endorsed by 19 research organisations representing 34 countries, these recommendations provide the framework to facilitate and harmonise data collection and sharing for HNC research. These variables have also been incorporated into a ready to use downloadable HNCIG minimum database, available from the HNCIG website.