Guidance Document Research Articles

A framework to support the application of the OECD guidance documents on (Q)SAR model validation and prediction assessment for regulatory decisions

Advances in the development and application of in silico models in toxicology has been recognised by two OECD guidance documents (69: Guidance Document On The Validation Of (Quantitative) Structure-Activity Relationship [(Q)SAR] Models and 386: (Q)SAR Assessment Framework: Guidance for the regulatory assessment of (Q)SAR models, predictions, and results based on multiple predictions) published in 2007 and 2023 respectively. The former outlines criteria for appropriate model validation, whilst the latter provides guidance around assessing predictions derived from them. The concepts and criteria described within these guidelines have been used to establish a framework to support both model builders and those applying them to support regulatory decisions. Herein we demonstrate how to meet those criteria and propose where further guidance is essential for ensuring the consistent, confident, and safe application of in silico models in support of regulatory decisions.

Developing a reporting item checklist for studies of HIV drug resistance prevalence or incidence: a mixed methods study

BackgroundAdequate surveillance of HIV drug resistance prevalence is challenged by heterogenous and inadequate data reporting. To address this issue, we recently published reporting guidance documentation for studies of HIV drug...

Leveraging COVID-19 Vaccine Safety Monitoring in Ethiopia and Pakistan to Enhance System-Wide Safety Surveillance.

The rapid development, introduction, and global uptake of COVID-19 vaccines required countries to have strong pharmacovigilance systems in place to monitor and address adverse events following immunization (AEFIs). These systems provide timely data on vaccine safety that support decisions about the potential risks of vaccine adverse events relative to the benefit of disease prevention. In Ethiopia, the monitoring system was limited by the lack of data being submitted through its passive surveillance system, delays in investigating serious adverse events and conducting causality assessments, and the lack of reporting to the World Health Organization (WHO) global database, VigiBase. In Pakistan, the pharmacovigilance system lacked reporting requirements and guidance documentation, regulatory policies were insufficient, and staff lacked the capacity to evaluate AEFI reports. Several interventions were implemented in both countries to improve pharmacovigilance systems and processes necessary to collect, analyze, and report AEFIs from health care facilities to the national level and facilitate the use of global and national electronic reporting tools. In addition, Pakistan improved the regulatory policy environment and engaged vaccine manufacturers and private sector health facilities in AEFI reporting for the first time in the country. Outcomes include an increased number of COVID-19 vaccine-related AEFIs reported and causality assessments completed, which means that potential safety issues were being analyzed more quickly, comprehensively, and accurately. The number of AEFI reports submitted to VigiBase by Pakistan's regulatory authority more than quintupled from approximately 5,000/quarter in 2021 to 28,555/quarter in 2022. In Ethiopia, by October 2022, 44,000 AEFI reports had been received, and 40 causality assessments completed. In both countries, timely AEFI data review and analysis led to prompt recommendations and regulatory actions, highlighting the far-reaching implications of strengthening the country-level pharmacovigilance systems. These strengthened systems are now in place for use with all vaccines.

Practical considerations to optimize aquatic testing of particulate material, with focus on nanomaterials

Following available approaches included e.g., in existing OECD Test Guidelines and Guidance Documents for the aquatic testing of particulate materials such as nanomaterials and microplastics leads to various challenges to be considered.

Interlaboratory validation of the ToxTracker assay: An in vitro reporter assay for mechanistic genotoxicity assessment.

ToxTracker is a mammalian cell reporter assay that predicts the genotoxic properties of compounds with high accuracy. By evaluating induction of various reporter genes that play a key role in relevant cellular pathways, it provides insight into chemical mode-of-action (MoA), thereby supporting discrimination of direct-acting genotoxicants and cytotoxic chemicals. A comprehensive interlaboratory validation trial was conducted, in which the principles outlined in OECD Guidance Document 34 were followed, with the primary objectives of establishing transferability and reproducibility of the assay and confirming the ability of ToxTracker to correctly classify genotoxic and non-genotoxic compounds. Reproducibility of the assay to predict genotoxic MoA was confirmed across participating laboratories and data were evaluated in terms of concordance with in vivo genotoxicity outcomes. Seven laboratories tested a total of 64 genotoxic and non-genotoxic chemicals that together cover a broad chemical space. The within-laboratory reproducibility (WLR) was up to 98% (73%-98% across participants) and the overall between-laboratory reproducibility (BLR) was 83%. This trial confirmed the accuracy of ToxTracker to predict in vivo genotoxicants with a sensitivity of 84.4% and a specificity of 91.2%. We concluded that ToxTracker is a robust in vitro assay for the accurate prediction of in vivo genotoxicity. Considering ToxTracker's robust standalone accuracy and that it can provide important information on the MoA of chemicals, it is seen as a valuable addition to the regulatory in vitro genotoxicity battery that may even have the potential to replace certain currently used in vitro battery assays.

Technological features of OOG transportation by sea transport

The article discusses the features of the transportation of oversized cargo by sea on container ships. The main governing documents and rules for the confirmation and placement of oversized cargo are indicated. The problems are reflected in the guidance documentation, since at the moment it is impossible to take into account all the features of a specific oversized cargo when creating a loading plan and cargo fastening tools on a flat rack. The scheme of placement of oversized cargo on a container ship is given. Options for attaching oversized cargo to a flat rack are considered in detail. The loads are divided into categories, for each of which the methods of fastening are given in accordance with the peculiarities of the geometric shapes of the load and the weight distribution. The conclusion indicates the need to create a software module for standardizing the rules for loading oversized cargo, which will systematize all the characteristics of oversized cargo, calculate the best options for placing cargo on a ship, taking into account the safety requirements and optimality of the cargo plan, reduce accidents during loading / unloading and transportation. It was also noted that the standardization of the loading module for oversized cargo will allow integrating information about the transportation of oversized cargo into the overall system for determining the efficiency and quality of container shipping.

Introduction to School Medicaid for School Nurses.

School nurses are important participants in School Medicaid (SM) programs nationally. Yet, the complexity of SM programs and required documentation are major barriers to implementing this program for nurses. School nurses are often required to participate in the SM program without having a clear understanding of the purpose and components of the overall program. With the expansion of SM programs due to the Centers for Medicare and Medicaid Services "free care" guidance change, nursing services and documentation are receiving more attention and scrutiny as more nursing services become eligible for reimbursement in states across the country. This article presents a clear overview of SM, its history, different components of state SM programs, school nursing documentation and challenges, and resources for school nurses who are interested in more information.

Management of RANKL-mediated Disorders With Denosumab in Children and Adolescents: A Global Expert Guidance Document.

Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents. This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders. Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document. Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available. Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks.

Pharmacokinetic/pharmacodynamic evaluation of tigecycline dosing in a hollow fiber infection model against clinical bla-KPC producing Klebsiella Pneumoniae isolates

The FDA announced a boxed warning for tigecycline due to progression of infections caused by Gram-negative bacteria and increased risk of mortality during treatment. Plasma exposure of tigecycline might not prevent bacteraemia in these cases from the focuses. Hence, we evaluated intensified dosing regimens and breakpoints that might suppress bloodstream infections, caused by progression of infection by e.g., Gram-negatives. A pharmacometric model was built from tigecycline concentrations (100–600 mg daily doses) against clinical Klebsiella pneumoniae isolates (MIC 0.125–0.5 mg/L). Regrowth occurred at clinically used doses and stasis was only achieved with 100 mg q8h for the strain with the lowest studied MIC of 0.125 mg/L. Stasis at 24 h was related to fAUC/MIC of 38.5. Our study indicates that even intensified dosing regimens might prevent bloodstream infections only for MIC values ≤0.125 mg/L for tigecycline. This indicates an overly optimistic breakpoint of 1 mg/L for Enterobacterales, which are deemed to respond to the tigecycline high dose regimen (EUCAST Guidance Document on Tigecycline Dosing 2022).

Promoting Coordination and Collaboration in Tribal Home Visiting Programs in the United States.

A joint statement from two federal agencies in the United States calls for coordination and collaboration between programs serving families of infants and toddlers who are at risk or developmentally delayed or disabled U.S. Department of Education and U.S. Department of Health and Human Services. Policy guidance: Joint statement on collaboration and coordination of the MIECHV and IDEA Part C programs. (2017). Individuals with Disabilities Education Act. ED/HHS Joint Guidance Document: Collaboration and Coordination of the Maternal, Infant, and Early Childhood Home Visiting Program and the Individuals with Disabilities Education Act Part C Programs. Young Native American children living on tribal lands in this country are currently eligible for two federal programs associated with these agencies which overlap in mission and implementation. This paper outlines potential strategies for creating a more seamless system of services for tribal families involving more centralized intake processes and procedures, cross training of staff to work across programs, and adopting more unifying approaches to program implementation. A streamlined system of services will result in interventions that better support family and child outcomes while reducing duplication of services, consolidating the limited number of qualified professionals available to provide services, and increasing convenience and cultural attunement of services to Native American families currently participating in both programs.

Guidance on the assessment of pesticide residues in rotational crops.

EFSA has prepared a guidance document on the assessment of studies on the nature and magnitude of pesticide residues in rotational crop studies as defined in Section 6.6 of the Annex to Regulation (EU) No 283/2013. This guidance document supports the practical implementation of the relevant OECD Test Guidelines (TGs) and OECD Guidance Documents in a harmonised way, respecting the EU regulatory framework for the pesticide assessments. The individual steps of the assessment are illustrated by examples, figures and flow charts. Sources of uncertainty in these assessments are identified and recommendations for further work are provided.

A Descriptive Review of Occupational Therapy Education.

This AOTA Guidance Document describes the present state of occupational therapy education within the United States educational system.

Application of Artificial Intelligence in Orthodontics: Current State and Future Perspectives.

In recent years, there has been the notable emergency of artificial intelligence (AI) as a transformative force in multiple domains, including orthodontics. This review aims to provide a comprehensive overview of the present state of AI applications in orthodontics, which can be categorized into the following domains: (1) diagnosis, including cephalometric analysis, dental analysis, facial analysis, skeletal-maturation-stage determination and upper-airway obstruction assessment; (2) treatment planning, including decision making for extractions and orthognathic surgery, and treatment outcome prediction; and (3) clinical practice, including practice guidance, remote care, and clinical documentation. We have witnessed a broadening of the application of AI in orthodontics, accompanied by advancements in its performance. Additionally, this review outlines the existing limitations within the field and offers future perspectives.

AOP Report: Glutathione Conjugation Leading to Reproductive Dysfunction via Oxidative Stress.

We propose an adverse outcome pathway (AOP) for reproductive dysfunction via oxidative stress (OS). The AOP was developed based on Organisation for Economic Co-operation and Development (OECD) Guidance Document 184 and on the specific considerations of the OECD users' handbook supplement to the guidance document for developing and assessing AOPs (no. 233). According to the qualitative and quantitative experimental data evaluation, glutathione (GSH) conjugation is the first upstream key event (KE) of this AOP to reproductive dysfunction triggering OS. This event causes depletion of GSH basal levels (KE2 ). Consequently, this drop of free GSH induces an increase of reactive oxygen species (KE3 ) generated by the natural cellular metabolic processes (cellular respiration) of the organism. Increased levels of these reactive species, in turn, induce an increase of lipid peroxidation (KE4 ). This KE consequently leads to a rise in the amount of toxic substances, such as malondialdehyde and hydroxynonenal, which are associated with decreased quality and competence of gamete cell division, consequently impairing fertility (KE5 and adverse outcome). The overall assessment of the general biological plausibility, the empirical support, and the essentiality of KE relationships was considered as high for this AOP. We conclude that GSH conjugation is able to lead to reproductive disorder in fishes and mammals, via OS, but that the amount of stressor needed to trigger the AOP differs between stressors. Environ Toxicol Chem 2023;42:2519-2528. © 2023 SETAC.

Current Approaches to the Preclinical Assessment of Endocrine Toxicity

Scientific relevance. Endocrine disruptors affect the functioning of endocrine organs, which leads to adverse drug reactions. Endocrine toxicity requires special attention in preclinical studies of candidate medicinal products.Aim. The study aimed to review international guidelines and approaches to assessing the risk of endocrine toxicity associated with medicinal products.Discussion. This review covers documents that provide a methodological framework for identifying and classifying a chemical compound as an endocrine disruptor. These documents include the following: Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption (Organisation for Economic Cooperation and Development, 2018), Nonclinical Evaluation of Endocrine-Related Drug Toxicity (Food and Drug Administration, 2015), and Guidance for the Identification of Endocrine Disruptors in the Context of Regulations (EU) No. 528/2012 and (EC) No. 1107/2009. The proposed algorithm for endocrine toxicity assessment involves collecting all available data on the test compound, such as the literature and previously obtained experimental data, including acute and subchronic toxicity data, and in silico predictions. Particular attention should be paid to the standard battery of preclinical chronic toxicity studies, which can identify most side effects associated with the endocrine system. The main endpoints for endocrine toxicity include changes in the mass and histopathology of the major endocrine organs (adrenal glands, testes, epididymides, ovaries, and the thyroid gland), oestrous cycle effects, reproductive toxicity, and transplacental action. A thorough assessment of the data obtained provides for the determination of unfavourable endocrine activity that requires further studies.Conclusions. The OECD guidelines offer a set of validated in vivo and in vitro tests that characterise the most important mechanisms of endocrine toxicity (oestrogen, androgen, thyroid, and steroidogenic endocrine pathways) by identified toxic effects. This approach allows researchers to identify potential endocrine disorders early in the drug development process and to optimise the scope of the required studies accordingly.

A disease model predicting placebo response and remission status of patients with ulcerative colitis using modified Mayo score.

The Mayo Clinical Score is used in clinical trials to describe the clinical status of patients with ulcerative colitis (UC). It comprises four subscores: rectal bleeding (RB), stool frequency (SF), physician's global assessment, and endoscopy (ENDO). According to recent US Food and Drug Administration guidelines (Ulcerative colitis: developing drugs for treatment, Guidance Document, https://www.fda.gov/regulatory-information/s. 2022), clinical response and remission should be based on modified Mayo Score (mMS) relying on RB, SF, and ENDO. Typically, ENDO is performed at the beginning and end of each phase, whereas RB and SF are more frequently available. Item response theory (IRT) models allow the shared information to be used for prediction of all subscores at each observation time; therefore, it leverages information from RB and SF to predict ENDO. A UC disease IRT model was developed based on four etrolizumab phase III studies to describe the longitudinal mMS subscores, placebo response, and remission at the end of induction and maintenance. For each subscore, a bounded integer model was developed. The placebo response was characterized by a mono-exponential function acting on all mMS subscores similarly. The final model reliably predicted longitudinal mMS data. In addition, remission was well-predicted by the model, with only 5% overprediction at the end of induction and 3% underprediction at the end of maintenance. External evaluation of the final model using placebo arms from five different studies indicated adequate performance for both longitudinal mMS subscores and remission status. These results suggest utility of the current disease model for informed decision making in UC clinical development, such as assisting future clinical trial designs and evaluations.

Introducing best practice for reproducibility in government

There is an appetite to improve the reproducibility of quantitative analysis undertaken across government. Our team supports conversion of regular publications into Reproducible Analytical Pipelines (RAP). To achieve this, we developed a roadmap to work with analysts in our organisation and help them transform their pipelines and build their skills.
 An audit of the current RAP status of all regular pipelines assisted in resource allocation and planning. The maturity of a RAP is evaluated on 7 criteria required to reach a minimum viable product (MVP) and 7 additional advanced criteria as outlined by the Analysis Function (AF). We use a combination of hands-on pair-coding with analysis teams, regular and ad hoc code reviews, and training sessions to convert existing pipelines into RAPs, while simultaneously upskilling the analysts. We have also developed guidance and training documentation to share internally and externally.
 Currently, out of 73 regular publications, 12 have reached the MVP, with an average score of 4.36 out of 7. This scoring is reassessed monthly, allowing us to track the progress in real-time. Self-assessment of technical skills increased by between 43% and 89% and 97% said their understanding of RAP principals improved because of the training and 77% said they are now able to implement best practice into their work. By working with the pipeline owners instead of just refactoring the code directly, we are ensuring business resilience. The in-depth knowledge of the pipeline and skills required to maintain it are present within the analysis team. Publishing our methods, documentation and tools facilitates adoption of RAP for those without a dedicated RAP team.
 We are on track to convert all our regular publications into RAPs and move to “RAP by default”, in line with the AF RAP Strategy. This will improve the reproducibility, quality, efficiency, transparency, and trustworthiness of analysis within government. We hope other organisations can learn from our methods.

Development of Two Korean IACUC Guidance Documents to Foster Implementation of the Three Rs.

In Korea, Institutional Animal Care and Use Committees (IACUCs) have been legally required to apply the Three Rs principles (i.e. replacement, reduction and refinement) and undertake the ethical review of animal study protocols, since 2008. According to Korean law, each IACUC is required to appoint at least one lay member recommended by a non-governmental animal protection organisation, who participates in the ethical review process as part of this role. Despite the importance of the Three Rs and the ethical review process, limited information and practical resources are available for IACUC members in the Korean language, particularly for lay members who are inexperienced in animal experimentation. In January 2020, the Animal and Plant Quarantine Agency announced the funding for a six-month research project to develop guidance to assist IACUC members in carrying out effective and efficient protocol reviews in line with Korean legislative requirements. This funding was awarded for the production of two IACUC guidance documents - 'Guide for Animal Study Protocols' and 'Guide for the IACUC Lay Member' - which were published in December 2020. These guidance documents aim to foster the implementation of the Three Rs and provide practical resources for IACUC members, researchers and other relevant personnel. This paper describes the framework for animal use in Korea and the overall production of these two IACUC Guidance Documents.

AACC/NKF Guidance Document on Improving Equity in Chronic Kidney Disease Care.

Kidney disease (KD) is an important health equity issue with Black, Hispanic, and socioeconomically disadvantaged individuals experiencing a disproportionate disease burden. Prior to 2021, the commonly used estimated glomerular filtration rate (eGFR) equations incorporated coefficients for Black race that conferred higher GFR estimates for Black individuals compared to non-Black individuals of the same sex, age, and blood creatinine concentration. With a recognition that race does not delineate distinct biological categories, a joint task force of the National Kidney Foundation and the American Society of Nephrology recommended the adoption of the CKD-EPI 2021 race-agnostic equations. This document provides guidance on implementation of the CKD-EPI 2021 equations. It describes recommendations for KD biomarker testing, and opportunities for collaboration between clinical laboratories and providers to improve KD detection in high-risk populations. Further, the document provides guidance on the use of cystatin C, and eGFR reporting and interpretation in gender-diverse populations. Implementation of the CKD-EPI 2021 eGFR equations represents progress toward health equity in the management of KD. Ongoing efforts by multidisciplinary teams, including clinical laboratorians, should focus on improved disease detection in clinically and socially high-risk populations. Routine use of cystatin C is recommended to improve the accuracy of eGFR, particularly in patients whose blood creatinine concentrations are confounded by processes other than glomerular filtration. When managing gender-diverse individuals, eGFR should be calculated and reported with both male and female coefficients. Gender-diverse individuals can benefit from a more holistic management approach, particularly at important clinical decision points.

Implementing approaches to account for metal bioavailability in freshwaters: Current status and future directions.

Implementing approaches to account for metal bioavailability in freshwaters: Current status and future directions.