Global Harmonization Research Articles

Analytical method validation for biomarkers as a drug development tool: points to consider.

Biomarkers are an important drug developmental tool. Assessment of quantitative analytical methods of biomarkers is not included in any regulatory documents in Japan. Use of biomarkers in clinical evaluations and supporting the post-marketing evaluation of drug efficacy and/or adverse reactions requires assessment and full validation of analytical methods for these biomarkers. The Biomarker Analytical Method Validation Study Group is a research group in Japan comprising industry and regulatory experts. Group members discussed and prepared this 'points to consider document' covering measurements of endogenous metabolites/peptides/proteins by ligand binding assays and chromatographic methods with or without mass spectrometry. We hope this document contributes to the global harmonization of biomarker assay validation.

Occupational Cohort Studies in North America: Opportunities for Collaboration with OMEGA-NET partners

BACKGROUND AND AIM: While establishing and maintaining occupational cohorts is resource-intensive, findings from these studies often provide the basis for evidence-based policy decisions. The global harmonization of occupational cohort studies, as proposed by the OMEGA-NET project, will increase their value. This presentation provides an overview of selected U.S. and Canadian occupational cohorts, highlighting international collaborations. We will also discuss characteristics of successful international collaborations in progress, and some of the challenges. METHODS: The National Institute for Occupational Safety and Health has over 70 industrial cohorts representing a range of exposures including metals, organic compounds, particles and physical agents. Inclusion criteria vary and cohort sizes range from a few hundred to over 100,000. Many cohorts have detailed exposure histories and job-exposure matrices. In the U.S., cause of death and cancer incidence are determined by linkage with the U.S. National Death Index and state-based cancer registries, respectively. In Canada, cohort studies focused on specific industries (e.g. mining or forestry) or very large multi-industry cohorts have been conducted using national mortality and tumor registry or provincial medical record linkages. RESULTS:Several North American occupational cohorts currently participate in international pooled studies, including the International Nuclear Workers Study (INWORKS; n=308,000); the Pooled Uranium Miner Analysis (PUMA; n=120,000); and A Consortium of Agricultural Cohorts (AGRICOH; 22 cohorts). Potential cohorts that could involve global collaboration include workers exposed to engineered nanomaterials, firefighters, flight crew, and styrene. Challenges of pooling data include privacy concerns, and institutional restrictions on data sharing. Benefits of encouraging OMEGA-NET users to include North American occupational cohorts in pooled studies include the increased ability to investigate effect heterogeneity due to diversity of participants. CONCLUSIONS:Occupational exposures are among the most important modifiable risk factors in public health. The OMEGA-NET activity promotes collaborative and harmonized research that will enable evidence-based decision-making to reduce occupational disease. KEYWORDS: Cancer, International Pooled Studies, Occupational

PD-0899 Report dose-to-medium in clinical trials; a consensus from the Global Harmonisation Group

PD-0899 Report dose-to-medium in clinical trials; a consensus from the Global Harmonisation Group

In silico prediction of the full United Nations Globally Harmonized System eye irritation categories of liquid chemicals by IATA-like bottom-up approach of random forest method

ABSTRACT As an alternative to in vivo Draize rabbit eye irritation test, this study aimed to construct an in silico model to predict the complete United Nations (UN) Globally Harmonized System (GHS) for classification and labeling of chemicals for eye irritation category [eye damage (Category 1), irritating to eye (Category 2) and nonirritating (No category)] of liquid chemicals with Integrated approaches to testing and assessment (IATA)-like two-stage random forest approach. Liquid chemicals (n = 219) with 34 physicochemical descriptors and quality in vivo data were collected with no missing values. Seven machine learning algorithms (Naive Bayes, Logistic Regression, First Large Margin, Neural Net, Random Forest (RF), Gradient Boosted Tree, and Support Vector Machine) were examined for the ternary categorization of eye irritation potential at a single run through 10-fold cross-validation. RF, which performed best, was further improved by applying the ‘Bottom-up approach’ concept of IATA, namely, separating No category first, and discriminating Category 1 from 2, thereafter. The best performing training dataset achieved an overall accuracy of 73% and the correct prediction for Category 1, 2, and No category was 80%, 50%, and 77%, respectively for the test dataset. This prediction model was further validated with an external dataset of 28 chemicals, for which an overall accuracy of 71% was achieved.

Performance of the GHS Mixtures Equation for Predicting Acute Oral Toxicity

Acute oral toxicity classifications are based on the estimated chemical dose causing lethality in 50 % of laboratory animals tested (LD50). Given the large number of pesticide registration applications that require acute toxicity data, an alternative to the in vivo test could greatly reduce animal testing. The United Nations Globally Harmonized System of Classification and Labelling of Chemicals (GHS) Mixtures Equation estimates the acute toxicity of mixtures using the toxicities of mixture components. The goal of this study was to evaluate the concordance of LD50s predicted using the GHS Mixtures Equation and LD50s from the in vivo test results. Using the EPA classification system, concordance was 55 % for the full dataset (N = 671), 52 % for agrochemical formulations (N = 620), and 84 % for antimicrobial cleaning products (N = 51). Most discordant results were from substances LD50 > 2000 mg/kg (limit test) or 2000 < LD50 < 5000 mg/kg that were predicted as LD50 > 5000 mg/kg. A supplementary analysis combining all formulations with an LD50 > 500 mg/kg produced a concordance of 82 %. The lack of more toxic formulations in this dataset prevented a thorough evaluation of the GHS equation for such substances. Accordingly, our results suggest the GHS equation is helpful to predict the toxicity of mixtures, particularly those with lower toxicity.

Performance of the Abbott SARS-CoV-2 IgG II Quantitative Antibody Assay Including the New Variants of Concern, VOC 202012/V1 (United Kingdom) and VOC 202012/V2 (South Africa), and First Steps towards Global Harmonization of COVID-19 Antibody Methods.

ABSTRACTIn the initial stages of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, a plethora of new serology tests were developed and introduced to the global market. Many were not evaluated rigorously, and there is a significant lack of concordance in results across methods. To enable meaningful clinical decisions to be made, robustly evaluated, quantitative serology methods are needed. These should be harmonized to a primary reference material, allowing for the comparison of trial data and improved clinical decision making. A comprehensive evaluation of the new Abbott IgG II anti-SARS-CoV-2 IgG method was undertaken using CLSI-based protocols. Two different candidate primary reference materials and verification panels were assessed with a goal to move toward harmonization. The Abbott IgG II method performed well across a wide range of parameters with excellent imprecision (<3.5%) and was linear throughout the positive range (tested to 38,365 AU/ml). The sensitivity (based on ≥14-day post-positive reverse transcription-PCR [RT-PCR] samples) and specificity were 98.3% (90.6% to 100.0%) and 99.5% (97.1% to 100%), respectively. The candidate reference materials showed poor correlation across methods, with mixed responses noted in methods that use the spike protein versus the nucleocapsid proteins as their binding antigen. The Abbott IgG II anti-SARS-CoV-2 measurement appears to be the first linear method potentially capable of monitoring the immune response to natural infection, including from new emerging variants. The candidate reference materials assessed did not generate uniform results across several methods, and further steps are needed to enable the harmonization process.

PSY6-4 Regulatory aspect of regional collaboration for medical products development in Asia

It's been a while since access to medicines and other essential medical products was recognized as one of the important agenda in global health. COVID-19 pandemic has been affecting every parts of the world and never before has international concord to facilitate development and to achieve access to new medical products been requested to tackle this ongoing threat regardless of development stage of each country. Regulatory authorities play a key role to assure quality, safety and efficacy of medical products. ICH and IMDRF composing of regulatory authorities including US FDA, EMA and MHLW/PMDA have long been leading global harmonization activities that minimize regulatory deviation among regulatory authorities and enable to develop medical products on a common ground. APEC's Regulatory Harmonization Steering Committee under the Life Sciences Innovation Forum further promotes it in Asia pacific region, making full use of deliverables of those initiatives. In addition to PMDA's participation in those global and regional initiatives, PMDA has been contributing to implementation of regulatory harmonization and reliance principle by providing training programs to regulators through Asia Training Center for Pharmaceuticals and Medical Devices Regulatory Affairs (PMDA-ATC) established in 2016. Moreover, with a recognition that access to medical products particularly in Asian region is essential for the realization of Universal Health Coverage (UHC), which is regarded as an integral part of Japan's contribution in global health, the Headquarters for the Healthcare Policy of Japan approved the Grand Design for Asian Pharmaceutical and Medical Devices Regulatory Harmonization in 2019 aiming at concretizing regulatory harmonization to contribute to the health of people in Asia. In accordance with the Grand Design, PMDA reorganized Office of International Programs and further contributes to regulatory harmonization in Asian region through multi- and bilateral cooperation.

Application of the Validated In Vitro Reconstructed Human Skin and Eye Models For Hazard Identification of the Chemical Mixtures

The international and national directives and legislation requires to perfom validated in vitro alternative methods to animal testing of chemicals and mixtures for predictible and precise evoluation of toxicity in human. The regulatory agencies require the hazard assessment on skin and ocular as reported by the United Nations, Globally Harmonized System (UN GHS) of Classification and Labeling of Chemicals. To address this need and investigate the usage of alternative methods, the five representative chemical mixtures were prepared in different compositions and their toxicity was evaluated using in vitro validated EpiDerm™ SCT for skin corrosion, EpiDerm™ SIT for skin irritation, and EpiOcular™ OCL for eye irritation. The tested chemical mixtures 1 and 3 were found corrosive for skin and irritant for both skin and eye. They were identified in the category 1 according to UN GHS. The tested chemical mixtures 2, 4, and 5 were found to be neither corrosive nor irritant to the skin and eye. They were identified in the UN GHS No Category. The potential usage of in vitro Reconstructed Human Epidermis and Cornea-like Epithelial as a replacement to animal testing contributed significantly to classify the ocular and skin irritation/corrosion of liquid and solid chemical mixtures and to comply with the regulatory testing requirements. This study confirm that the use of alternative assays instead of conventional in vivo animal test methods could be very reliable and accurate tool to evaluate the skin and eye irritation/corrosion for hazard identification of chemical mixtures.

CEQAT-DGHS interlaboratory tests for chemical safety: Validation of laboratory test methods by determining the measurement uncertainty and probability of incorrect classification including so-called “Shark profiles”

Laboratory test results are of vital importance for correctly classifying and labelling chemicals as “hazardous” as defined in the UN Globally Harmonized System (GHS)/EC CLP Regulation or as “dangerous goods” as defined in the UN Recommendations on the Transport of Dangerous Goods. Interlaboratory tests play a decisive role in assessing the reliability of laboratory test results. Interlaboratory tests performed over the last 10 years have examined different laboratory test methods. After analysing the results of these interlaboratory tests, the following conclusions can be drawn: 1There is a need for improvement and validation for all laboratory test methods examined. 2To avoid any discrepancy concerning the classification and labelling of chemicals, the use of validated laboratory test methods should be state of the art, with the results accompanied by the measurement uncertainty and (if applicable) the probability of incorrect classification.This paper addresses the probability of correct/incorrect classification (for example, as dangerous goods) on the basis of the measurement deviation obtained from interlaboratory tests performed by the Centre for quality assurance for testing of dangerous goods and hazardous substances (CEQAT-DGHS) to validate laboratory test methods. This paper outlines typical results (e.g. so-called “Shark profiles” – the probability of incorrect classification as a function of the true value estimated from interlaboratory test data) as well as general conclusions and steps to be taken to guarantee that laboratory test results are fit for purpose and of high quality.

Normative framework of informed consent in clinical research in Germany, Poland, and Russia

BackgroundBiomedical research nowadays is increasingly carried out in multinational and multicenter settings. Due to disparate national regulations on various ethical aspects, such as informed consent, there is the risk of ethical compromises when involving human subjects in research. Although the Declaration of Helsinki is the point of reference for ethical conduct of research on humans, national normative requirements may diverge from its provisions. The aim of this research is to examine requirements on informed consent in biomedical research in Germany, Poland, and Russia to determine how each national regulatory framework relates to the provisions of the Declaration of Helsinki.MethodsFor this analysis, we conducted a search of the legal databases “Gesetze im Internet” for Germany, “Internetowy System Aktow Prawnych” for Poland, and “ГAPAHT – Garant” for Russia. The search was complemented by a review of secondary literature contained in the databases Google Scholar, PubMed, Polish National Library, and eLibrary.ru. We have identified 21 normative regulations containing provisions on informed consent in clinical research in all three countries. The content of these documents was systematically categorized and analyzed.ResultsThe normative framework in all three countries shows a strong commitment towards the core ethical principles of research envisaged in the Declaration of Helsinki. Nevertheless, provisions on informed consent vary between these three countries. The differences range from the method and language in which information should be provided, through the amount of information required to be disclosed, to the form of documenting consent or withdrawal. In the case of research on vulnerable groups, these differences are particularly visible.ConclusionsThe identified differences can negatively impact the ethical conduct of international clinical studies. Attention needs to be paid that flexibilities within national regulations are not misused to undermine the protection of research subjects. Achieving global or regional legislative harmonization might prove impossible. Such lack of legal consensus reinforces the significance of the international ethical agreements.Trial registration: Not applicable.

The First WHO International Standard for Adalimumab: Dual Role in Bioactivity and Therapeutic Drug Monitoring.

The expanded availability of adalimumab products continues to widen patient access and reduce costs with substantial benefit to healthcare systems. However, the long-term success of these medicines is highly dependent on maintaining consistency in quality, safety and efficacy while minimizing any risk of divergence during life-cycle management. In recognition of this need and demand from global manufacturers, the World Health Organization (WHO) Expert Committee on Biological standardization established the WHO 1st International standard (IS) for Adalimumab (coded 17/236) in October 2019 with a defined unitage ascribed to each of the individual bioactivities evaluated in the study namely, TNF-α binding, TNF-α neutralization, complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity. For development of the IS, two candidate standards were manufactured as per WHO recommendations. Analysis of extensive datasets generated by testing of a common set of samples including the candidate standards by multiple stakeholders including regulatory agencies using their own qualified assays in a large international collaborative study showed comparable biological activity for the tested candidates for the different activities. Use of a common standard significantly decreased the variability of bioassays and improved agreement in potency estimates. Data from this study clearly supports the utility of the IS as an important tool for assuring analytical assay performance, for bioassay calibration and validation, for identifying and controlling changes in bioactivity during life-cycle management and for global harmonization of adalimumab products. In addition, in a separate multi-center study which included involvement of hospital and clinical diagnostic laboratories, the suitability of the adalimumab IS for therapeutic drug monitoring assays was examined by analysis of data from testing of a common blind coded panel of adalimumab spiked serum samples representative of the clinical scenario along with the IS and in-house standards in diverse immunoassays/platforms. Both commercially available and in-house assays that are routinely used for assessing adalimumab trough levels were included. Excellent agreement in estimates for adalimumab content in the spiked samples was observed regardless of the standard or the method with inter-laboratory variability also similar regardless of the standard employed. This data, for the first time, provides support for the extended applicability of the IS in assays in use for therapeutic drug monitoring based on the mass content of the IS. The adalimumab IS, in fulfilling clinical demand, can help toward standardizing and harmonizing clinical monitoring assays for informed clinical decisions and/or personalized treatment strategies for better patient outcomes. Collectively, a significant role for the adalimumab IS in assuring the quality, safety and efficacy of adalimumab products globally is envisaged.

The ecology of regulatory change: The security and exchange commission’s modernization of oil and gas reserves reporting

We examine the SEC's Modernization of Oil and Gas Reserve Reporting project (SEC, 2007) to ask the question who is involved and how in the evolution of oil and gas reserve reporting rules? We use this examination to map the regulatory ecology of the various entities involved, and ask further what does it suggest for similar regulatory reform in other jurisdictions in order to support international standardization? We find that the regulatory ecology is split into two linked professional regulatory ecologies: accounting/securities and engineering/geoscience. These two ecologies include professionals, professional bodies, standard setters, and other securities commissions. We also find that there is a gap in these regulatory ecologies, isolating the International Accounting Standards Board (IASB). This leads us to offer three propositions for regulators. First, continued revision is required to achieve international comparability in standards. Second, connecting accountancy and engineering practices serves global harmonization by helping securities regulators leverage these practices as regulations converge globally. And, third, such global harmonization has implications for policymakers concerned with energy policy, as political and practical divergences of reserve calculations can create incomparable oil reserve forecasts.

Defining Nutritional and Functional Niches of Legumes: A Call for Clarity to Distinguish a Future Role for Pulses in the Dietary Guidelines for Americans.

Legume food crops can contribute to the solution of diet-related public health challenges. The rich diversity of the botanical family Fabaceae (Leguminosae) allows legumes to fill numerous nutritional niches. Pulses (i.e., a subgroup of legumes including chickpeas, cowpeas, dry beans, dry peas, and lentils) are a nutrient-dense food that could play a key role in eliminating the dramatic underconsumption of dietary fiber and potassium, two dietary components of public health concern, all while maintaining a caloric intake that promotes a healthy weight status. However, incorrect use of terminology—in the commercial and scientific literature as well as in publications and materials prepared for the consuming public—creates confusion and represents a barrier to dissemination of clear dietary guideline messaging. The use of accurate terminology and a simple classification scheme can promote public health through differentiation among types of legumes, better informing the development and implementation of nutritional policies and allowing health care professionals and the public to capitalize on the health benefits associated with different legumes. Although inconsistent grouping of legumes exists across countries, the recently released 2020–2025 Dietary Guidelines for Americans (DGA) were chosen to illustrate potential challenges faced and areas for clarification. In the 2020–2025 DGA, pulses are included in two food groups: the protein food group and ‘beans, peas, lentils’ vegetable subgroup. To evaluate the potential of pulses to contribute to intake of key dietary components within calorie recommendations, we compared 100 kilocalorie edible portions of pulses versus other foods. These comparisons demonstrate the unique nutritional profile of pulses and the opportunity afforded by this type of legume to address public health concerns, which can be greatly advanced by reducing confusion through global harmonization of terminology.

Drug adulteration of sexual enhancement supplements: a worldwide insidious public health threat

Worldwide, the consumption of dietary supplements for the enhancement of sexual performance is common. Consumers are generally fond of these products because they often want to avoid drugs, preferring "natural" than "chemical" solutions. This is challenging, as many of these supplements labelled "herbal" or "natural" are actually adulterated with drugs, mainly phosphodiesterase-5 inhibitors. This phenomenon is facilitated by fewer demanding regulations for marketing supplements. Thus, consumers may be widely exposed to serious adverse events, such as acute liver injury, kidney failure, pulmonary embolism, stroke or even death. We aim to warn physicians about this issue. This multidisciplinary review simultaneously deals with clinical consequences of this phenomenon, analytical toxicology and regulation. Indeed, after outlining this worldwide issue and highlighting that a drug-adulterated dietary supplement is actually a falsified drug, we discuss its main contributing factors. Then, we describe some examples of adverse events of which a case of sildenafil-tadalafil-induced ischaemic stroke that benefited medical care in our hospital. Furthermore, we present some means to avoid adulteration and discuss their limitations that may be explained by the heterogeneity of the regulation of dietary supplements between countries. Doing so, we point out the requirement of a global harmonization of this regulation for an efficient eradication of this public health threat. Meanwhile, dietary supplements should be considered adulterated until proven otherwise. Thus, we encourage physicians to investigate these products in the drug histories of their patients, especially when clinical conditions cannot be explained by classical aetiologies.

Technology offers sustainable nutrition solutions

Technology offers sustainable nutrition solutions

Schemes and Performance Evaluation Criteria of Korean Association of External Quality Assessment (KEQAS) for Improving Laboratory Testing.

External quality assessment (EQA) is important for evaluating clinical laboratories and enhancing their testing quality. EQA schemes are variable; thus, it is crucial that the EQA organizers share their experiences to continuously improve the EQA scheme. The Korean Association of External Quality Assessment Service (KEQAS) has been the leading, authorized EQA institute for the standardization and quality management of laboratory testing in Korean medical institutions since 1976. The EQA scheme underwent a major change in 2016, and the number of EQA programs increased significantly since then. The key changes implemented in EQA scheme include a fully computerized assessment to accelerate feedback and unification of the testing and reporting methods. We provide an overview of the EQA schemes and performance evaluation criteria of the KEQAS and suggest directions for achieving the global harmonization of EQA.

An Overview of the Biopharmaceutics Classification System (BCS)

The Biopharmaceutics Classification System (BCS) is an essential tool in pharmaceutical sciences, providing a scientific framework for classifying drugs based on their solubility and permeability characteristics. This system, developed in 1995, helps streamline drug development and regulatory approval processes by predicting in vivo drug performance from in vitro data. This paper reviews the four BCS classes, their solubility and permeability criteria, detailed procedures for determining these characteristics, and suitable formulation strategies for each class. Additionally, it explores the concept of biowaivers, which allows for the waiver of in vivo bioavailability and bioequivalence studies under certain conditions, primarily for BCS Class I drugs. The advantages, challenges, and limitations of biowaivers are discussed, emphasizing the need for global harmonization to fully realize the BCS's potential.

Automated mass spectrometry multi-attribute method analyses for process development and characterization of mAbs

More than 370 biotherapeutics drug products have been approved by regulatory agencies on the US and EU markets and this industry continues to expand. Process change and optimization is necessary to develop new effective biologics in a cost effective and productive way. Consequently, improvement of analytical techniques is required for better product characterization according to Quality by Design (QbD) approach recommended by regulatory agencies. Recently, multi-attribute method (MAM) has emerged to meet such demands using mass spectrometry coupled to liquid chromatography (LC-MS). However, traditional sample preparation or data processing would not be suitable to guide process development, because one of the common challenges during development of analytical platforms is instrument or method variability which can cause deviation in results. Here, we show a new automated analytical platform for MAM implemented on 3 different sites: the components of MAM platform include automated sample preparation, LC-MS based MAM, and data treatment automation. To our knowledge, this is the first study to show global harmonization on automated MAM platforms and the inter-sites comparability including the automated sample preparation and LC-MS instrument. Also, we demonstrate the applicability of MAM to support cell line development, cell culture process development and downstream process development. We expect that this MAM platform will effectively guide process development across multiple projects.

Dossier Formación Inicial del Profesorado

El entorno global contemporáneo ha experimentado reconfiguraciones económicas, tecnológicas y sociales de especial relevancia para la transformación y armonización mundial, durante el cual, actualmente cursamos por una pandemia sanitaria a consecuencia del Covid-19 que da cuenta de este nuevo orden, sanitario y de responsabilidad social de la humanidad; en forma particular, ha trascendido en el redefinición de la sociedad posmoderna dos condiciones inherentes e indispensables para la educación, que adquieren un valor preponderante en y para el desarrollo social: Ser docente y Formar docentes.

ТРАНСФОРМАЦІЯ СУЧАСНИХ МЕТОДИК ФІНАНСОВОГО АНАЛІЗУ ЗВІТНОСТІ ОБ’ЄДНАНЬ ПІДПРИЄМСТВ

The main goal of this research is to identify those indicators of reporting of associations of enterprises that change their nature or content under the influence of consolidation against the background of the application of IFRS, as well as areas of transformation of methods of its analysis. The article reveals the essence of consolidated financial statements and the peculiarities of the process of its formation. Financial information becomes the main tool of communication and formation of business image of enterprises in the market environment. The carrier of such information is the financial statements, which are compiled according to international standards, which are constantly progressing and reforming. As a result, business owners have more and more freedom in its formation, despite the global harmonization of the list of indicators and their content, which allows you to present your business in a favorable light and assess those aspects of contractors that are most important for further cooperation. The main information needs of groups of users of consolidated financial statements are considered. The authors specify the areas of analysis of the financial and property condition of the group of enterprises according to the consolidated financial statements and substantiate the reasons for the need for their transformation. Some aspects of the analysis of the consolidated financial statements are characterized, which do not allow to form a correct idea of the financial and property condition of its individual elements. The accounting components of the consolidated financial statements are determined, which may distort the results of the coefficient analysis and indicators of their modification. The peculiarities of the analysis of such reporting are due to the transformations of the accounting content of its indicators - the reflection of contingent assets, liabilities, risks, possible costs and revenues. All components of analysis methods - horizontal, vertical, trend, and especially - coefficient - undergo certain changes. The need to disseminate cost-oriented approaches in the analysis of consolidated financial statements is substantiated.