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Archives of Toxicology Nov 2022Robust and efficient processes are needed to establish scientific confidence in new approach methodologies (NAMs) if they are to be considered for regulatory... (Review)
Review
Robust and efficient processes are needed to establish scientific confidence in new approach methodologies (NAMs) if they are to be considered for regulatory applications. NAMs need to be fit for purpose, reliable and, for the assessment of human health effects, provide information relevant to human biology. They must also be independently reviewed and transparently communicated. Ideally, NAM developers should communicate with stakeholders such as regulators and industry to identify the question(s), and specified purpose that the NAM is intended to address, and the context in which it will be used. Assessment of the biological relevance of the NAM should focus on its alignment with human biology, mechanistic understanding, and ability to provide information that leads to health protective decisions, rather than solely comparing NAM-based chemical testing results with those from traditional animal test methods. However, when NAM results are compared to historical animal test results, the variability observed within animal test method results should be used to inform performance benchmarks. Building on previous efforts, this paper proposes a framework comprising five essential elements to establish scientific confidence in NAMs for regulatory use: fitness for purpose, human biological relevance, technical characterization, data integrity and transparency, and independent review. Universal uptake of this framework would facilitate the timely development and use of NAMs by the international community. While this paper focuses on NAMs for assessing human health effects of pesticides and industrial chemicals, many of the suggested elements are expected to apply to other types of chemicals and to ecotoxicological effect assessments.
Topics: Animals; Ecotoxicology; Humans; Pesticides; Research Design; Risk Assessment
PubMed: 35987941
DOI: 10.1007/s00204-022-03365-4 -
Nucleic Acids Research Jul 2018Advancement in the field of computational research has made it possible for the in silico methods to offer significant benefits to both regulatory needs and requirements...
Advancement in the field of computational research has made it possible for the in silico methods to offer significant benefits to both regulatory needs and requirements for risk assessments, and pharmaceutical industry to assess the safety profile of a chemical. Here, we present ProTox-II that incorporates molecular similarity, pharmacophores, fragment propensities and machine-learning models for the prediction of various toxicity endpoints; such as acute toxicity, hepatotoxicity, cytotoxicity, carcinogenicity, mutagenicity, immunotoxicity, adverse outcomes pathways (Tox21) and toxicity targets. The predictive models are built on data from both in vitro assays (e.g. Tox21 assays, Ames bacterial mutation assays, hepG2 cytotoxicity assays, Immunotoxicity assays) and in vivo cases (e.g. carcinogenicity, hepatotoxicity). The models have been validated on independent external sets and have shown strong performance. ProTox-II provides a freely available webserver for in silico toxicity prediction for toxicologists, regulatory agencies, computational and medicinal chemists, and all users without login at http://tox.charite.de/protox_II. The webserver takes a two-dimensional chemical structure as an input and reports the possible toxicity profile of the chemical for 33 models with confidence scores, and an overall toxicity radar chart along with three most similar compounds with known acute toxicity.
Topics: Computational Biology; Drug-Related Side Effects and Adverse Reactions; Humans; Internet; Machine Learning; Risk Assessment; Software
PubMed: 29718510
DOI: 10.1093/nar/gky318 -
Nucleic Acid Therapeutics Jan 2023The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical... (Review)
Review
The nucleic acid therapeutics field has made tremendous progress in the past decades. Continuous advances in chemistry and design have led to many successful clinical applications, eliciting even more interest from researchers including both academic groups and drug development companies. Many preclinical studies in the field focus on improving the delivery of antisense oligonucleotide drugs (ONDs) and/or assessing their efficacy in target tissues, often neglecting the evaluation of toxicity, at least in early phases of development. A series of consensus recommendations regarding regulatory considerations and expectations have been generated by the Oligonucleotide Safety Working Group and the Japanese Research Working Group for the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S6 and Related Issues (WGS6) in several white papers. However, safety aspects should also be kept in sight in earlier phases while screening and designing OND to avoid subsequent failure in the development phase. Experts and members of the network "DARTER," a COST Action funded by the Cooperation in Science and Technology of the EU, have utilized their collective experience working with OND, as well as their insights into OND-mediated toxicities, to generate a series of consensus recommendations to assess OND toxicity in early stages of preclinical research. In the past few years, several publications have described predictive assays, which can be used to assess OND-mediated toxicity or to filter out potential toxic candidates before moving to phases of preclinical development, that is, animal toxicity studies. These assays also have the potential to provide translational insight since they allow a safety evaluation in human systems. Yet, small preliminary studies should also be considered to complement this early assessment. In this study, we summarize the state of the art and provide guidelines and recommendations on the different tests available for these early stage preclinical assessments.
Topics: Animals; Humans; Oligonucleotides, Antisense; Oligonucleotides; Pharmaceutical Preparations; Drug Evaluation, Preclinical
PubMed: 36579950
DOI: 10.1089/nat.2022.0061 -
British Journal of Clinical Pharmacology Jun 2012Adverse drug reactions are the fifth most frequent cause of deaths in developed countries, effectively a global epidemic. However, progress in ameliorating the problem...
Adverse drug reactions are the fifth most frequent cause of deaths in developed countries, effectively a global epidemic. However, progress in ameliorating the problem has been slow. Pharmacovigilance currently operates without clear objectives in relation to individual decisions, with no protocol (although risk management plans are a great step forward), with obscure materials and methods used for making decisions, with very limited reasoning and discussion, and little or no follow up and audit of the results. Problems include under-reporting, poor quality reports, underuse of the latest communications technology and suboptimal individual feedback to reporters. Assessment of causality is poor, impeding decision-making. After signal detection, more active measures to assess the risk to public health are needed. Other essential factors include precision about the ways in which data are prepared and transformed into databases, the recognition of secondary effects, which may be more obvious than the primary effect, but not so easy to link causally, and cognisance of all kinds of interactions. Areas that should be developed include pharmacoepidemiology, knowledge finding (through data mining), and communication and systems technology. The general way forward seems clear: a rigorous way of documenting all the steps, from getting reports of harms into regulatory databases to assessing their effects on public health, is essential and should be publicly reviewed for weaknesses. In turn, matters would be much improved by input on benefit/harm perceptions from patient groups, influencing decisions about what should be the true targets for regulatory and pharmacovigilance activities, avoiding second guessing by regulators.
Topics: Adverse Drug Reaction Reporting Systems; Communication; Data Mining; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacovigilance; Public Health
PubMed: 22360774
DOI: 10.1111/j.1365-2125.2012.04249.x -
Blood Jun 2013Standardized response criteria to interpret and compare clinical trials are needed for approval of new therapeutic agents by regulatory agencies. The European...
Standardized response criteria to interpret and compare clinical trials are needed for approval of new therapeutic agents by regulatory agencies. The European LeukemiaNet (ELN) response criteria for essential thrombocythemia (ET) and polycythemia vera (PV) issued in 2009 have been widely adopted as end points in a number of recent clinical trials. However, evidence exists that they do not predict response or provide clinically relevant measures of benefit for the patients. This article presents revised recommendations for assessing response in ET and PV provided by a working group established by ELN and International Working Group-Myeloproliferative Neoplasms Research and Treatment. New definitions of complete and partial remission incorporate clinical, hematological, and histological response assessments that include a standardized symptom assessment form and consider absence of disease progression and vascular events. We anticipate that these criteria will be adopted widely to facilitate the development of new and more effective therapies for ET and PV.
Topics: Consensus; Humans; International Agencies; Platelet Aggregation Inhibitors; Polycythemia Vera; Practice Guidelines as Topic; Societies, Medical; Thrombocythemia, Essential
PubMed: 23591792
DOI: 10.1182/blood-2013-01-478891 -
Foods (Basel, Switzerland) Jul 2020Food market globalization, food security as well as increasing consumer demand for safe, minimally processed and healthy food impose the need to establish new approaches...
Food market globalization, food security as well as increasing consumer demand for safe, minimally processed and healthy food impose the need to establish new approaches for identifying and assessing food quality markers. Nowadays, food industry stakeholders are challenged to assure food quality and safety without compromising several prerequisites such as sustainable and ecologically resilient food production, prolonged shelf life, satisfactory sensory quality, enhanced nutritional value and health-promoting properties. In addition, food fraud related to deliberate product mislabeling or economically intended adulteration is of major concern for both industry and regulatory authorities due to cost and public health implications. Notwithstanding the great number of state-of-the-art analytical tools available for quantifying food quality markers, their implementation results in highly complex and big datasets, which are not easily interpretable. In this context, chemometrics e.g., supervised and unsupervised multivariate exploratory analyses, design-of-experiment methodology, univariate or multivariate regression modelling etc., are commonly implemented as part of food process optimization and food quality assessment. In this Special Issue, we aimed to publish innovative research and perspective papers on chemometric-assisted case studies relating to food quality assessment, food authenticity, mathematical modelling and optimization of processes involved in food manufacturing.
PubMed: 32650365
DOI: 10.3390/foods9070897 -
Value in Health : the Journal of the... Sep 2021The value of real-world evidence (RWE) in medicines regulation and health technology assessment has been increasingly emphasized. Nevertheless, although RWE is...
The value of real-world evidence (RWE) in medicines regulation and health technology assessment has been increasingly emphasized. Nevertheless, although RWE is increasingly used, there has been limited systematic evidence of its value. A recent study that examined the role and impact of RWE in regulatory assessments conducted through the European Medicines Agency provided such evidence. Results of the study demonstrated RWE was important to decision making, particularly for certain questions such as the quantification of adverse events, the evaluation of risk minimization measures, and the assessment of product usage. The study suggested, however, that in many of the assessments further RWE would have been valuable and concluded that RWE has, as yet, played a limited role in hypothesis generation and in the assessment of medication effectiveness. This study had been possible only because of the transparency of the European Medicines Agency decision making. Ensuring transparency of RWE evidence collection, study design and conduct, and of decision making based on this evidence will facilitate further development of the uses and value of RWE. Keywords: benefit-risk assessment; medicines regulation; real-world evidence; regulatory decision making.
Topics: Decision Making; Evidence-Based Medicine; Government Regulation; Humans; Research Design; Risk Assessment; Technology Assessment, Biomedical; United States
PubMed: 34452702
DOI: 10.1016/j.jval.2021.03.020 -
ALTEX 2022New approach methodologies (NAMs) that do not use experimental animals are, in certain settings, entirely appropriate for assuring the safety of chemical ingredients,...
New approach methodologies (NAMs) that do not use experimental animals are, in certain settings, entirely appropriate for assuring the safety of chemical ingredients, although regulatory adoption has been slow. In this opinion article we discuss how scientific advances that utilize NAMs to certify systemic safety are available now and merit broader acceptance within the framework of next generation risk assessments (NGRA).
Topics: Animal Testing Alternatives; Animals; Chemical Safety; Risk Assessment
PubMed: 35796331
DOI: 10.14573/altex.2204281 -
Frontiers in Bioengineering and... 2015Risk assessment is a reasoned, structured approach to address uncertainty based on scientific and technical evidence. It forms the foundation for regulatory... (Review)
Review
Risk assessment is a reasoned, structured approach to address uncertainty based on scientific and technical evidence. It forms the foundation for regulatory decision-making, which is bound by legislative and policy requirements, as well as the need for making timely decisions using available resources. In order to be most useful, environmental risk assessments (ERAs) for genetically modified (GM) crops should provide consistent, reliable, and transparent results across all types of GM crops, traits, and environments. The assessments must also separate essential information from scientific or agronomic data of marginal relevance or value for evaluating risk and complete the assessment in a timely fashion. Challenges in conducting ERAs differ across regulatory systems - examples are presented from Canada, Malaysia, and Argentina. One challenge faced across the globe is the conduct of risk assessments with limited resources. This challenge can be overcome by clarifying risk concepts, placing greater emphasis on data critical to assess environmental risk (for example, phenotypic and plant performance data rather than molecular data), and adapting advances in risk analysis from other relevant disciplines.
PubMed: 26301217
DOI: 10.3389/fbioe.2015.00110