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High dose selection is a key methodological element in general toxicity studies of medicines. It determines the informative value of study results, the compliance with the principles of ethical and rational use of experimental animals, and the accuracy of predicting the safety of new medicines for human use. The literature data and the regulatory experience in evaluating preclinical study results suggest that the selection of an inappropriate high dose is a very common error in planning toxicity studies. This error leads to a significant or complete loss of the informative value of study results; the results become useless for assessing the safety of new medicinal products for human use.The aim of this study was to analyse the current regulatory requirements for high dose selection for general toxicity studies of medicines.The analysis suggests that unreasonably high doses may be selected for toxicity studies because methodological recommendations are prone to interpretation errors. Their potential for ambiguity stems from the absence of specific standardised upper limits for toxic doses or sufficiently clear dose selection criteria. Prerequisites for properly planning preclinical safety studies of new medicines include compliance with dose selection requirements of regulatory toxicology and implementation of a clinically and toxicologically sound decision-making algorithm.

The lack of approved paediatric medicines is a global problem. Since paediatric patients are a high-risk group, a developer of paediatric medicines needs to evaluate and minimise unjustified risks early in the development process.The aim of the study was to analyse the current regulatory and methodological framework for non-clinical research and identify key risk factors that need addressing in paediatric drug development in order to substantiate the safety of children. One of the main objectives of non-clinical safety assessment of a medicinal product intended for children is to identify undesirable effects on child growth and development. According to national and international methodological guidelines, the developer may obtain the most valuable information to decide whether it is safe to enrol children into a clinical trial from the safety data collected in clinical studies in adult subjects. If the safety data available from studies in mature animals and adult subjects are insufficient to evaluate the safety of the clinical trial for paediatric patients, the developer may consider conducting non-clinical studies in immature (juvenile) animals. A paediatric non-clinical testing programme should be in line with a comprehensive significance assessment of key risk factors carried out on a case-by-case basis using weight-of-evidence (WoE) analysis. The conclusion on the safety of a medicinal product for children should be based on risk assessment in relevant clinical and non-clinical studies.

Generally, preclinical studies of medicines conducted in accordance with national and international regulatory recommendations allow minimising the risks of detecting serious adverse events in patients at the stage of clinical trials. Nevertheless, current analytical trends motivate the development of new prognostic approaches aimed at improving the reliability and accuracy of safety assessments.The aim of this study was to develop and test methodological approaches to comprehensive preclinical assessment of the key risk factors associated with the use of medicinal products in humans and to mathematical prediction of the corresponding benefits and risks.Materials and methods: the study combined information analysis and statistics; it used consolidated preclinical data on the protective properties of fabomotizole and national and international regulatory documents describing the principles and methods of evidence-based medicine, in particular, Bayesian statistics and prognostic research methods.Results: The article presents mathematical approaches developed to confirm the statistical reliability and prognostic significance of the results of preclinical assessment of the safety of medicines, based on Bayesian statistics, in particular, the concepts of weight of evidence (WoE), information value (IV), and normalised density (ND). Depending on the volume of the evaluated data, the WoE can be used to determine the weight of evidence of single variables, as well as entire groups of variables from individual tests or whole test panels, considered in the studies of general toxic effects, reproductive toxicity, genotoxicity and other studies characterising the condition of vital organs when evaluating the safety of medicines.Conclusions: The developed methodology allows evaluating the entire volume of information obtained in preclinical studies of medicinal products. The criteria in the form of WoE and IV in preclinical safety assessment of medicines can be used to estimate the benefits and risks of using medicines, including the products developed specifically for children and pregnant women.

Current requirements for the registration dossier include submission of a preclinical (nonclinical) overview, including scientific literature data on preclinical studies and actual preclinical data on the medicinal product. For some groups of medicines, scientific literature data may be used instead of actual preclinical data, which may be redundant. One of the important functions of the scientific literature review is the analysis of updated preclinical information on the medicinal product, which reflects the product’s characteristics, supports conclusions on its efficacy or safety, and may affect the results of the benefit/risk assessment. The aim of the study was to determine the optimal format for presenting scientific literature data in a nonclinical overview that would reflect the methodological aspects of preclinical pharmacology and toxicology studies of medicines. The authors analysed the regulations of the Russian Federation and the Eurasian Economic Union containing requirements for the scientific literature review submitted instead of actual preclinical data as part of the registration dossier for a medicinal product. The authors also considered potential difficulties in preparing a nonclinical overview based on scientific literature. In order to systematise scientific literature data, it is recommended to provide pharmacodynamic, pharmacokinetic, and toxicological data using a format consistent with the common technical document. The proposed recommendations help to harmonise the process of preparation and design of a nonclinical overview which should contain data and facts enabling a reasoned assessment of the benefit/risk ratio. The standardised format of literature data presentation will help the developer prepare an adequate nonclinical overview and will speed up assessment of clinical trial or marketing authorisation applications.

The decoding of the DNA structure and development of new molecular methods of its analysis, as well as identification of specific genomic changes responsible for malignant transformation, have become the turning points in elaboration of novel anti-tumour drugs directed against molecular and genetic targets of tumor growth. Transition from empirical screening of agents inhibiting tumour cell proliferation to molecule-targeted analytical methods has raised a number of serious methodological issues regarding preclinical evaluation of novel medicines. The objective of this paper was to analyse general principles and features of preclinical efficacy and safety studies of different classes of modern anti-tumour drugs with a view to improve existing national guidelines. The paper reviews various aspects of preclinical studies of different classes of anti-tumour drugs (small molecule chemotherapy drugs, hormones and hormone antagonists, alkylating agents and antimetabolites, microbial and herbal medicines, as well as monoclonal antibodies). The article explores general principles of studying the drugs’ pharmacological activity in vitro, ex vivo, and in vivo, and evaluating their pharmacokinetic parameters. It describes various methods and models of research, summarises specific aspects of determination of genotoxicity, carcinogenicity, reproductive toxicity, mutagenicity, acute and chronic toxicity of various groups of medicines. It also lists criteria for selecting drug doses for toxicokinetic studies. The need for harmonisation of national requirements for conducting preclinical studies with the European standards entails alignment of terminology and further development of general algorithms for selecting doses and determining the necessary scope of research. The use of biomarkers in preclinical studies will make it possible to exclude inefficient compounds from further research.

Regulatory approaches to assessing the safety of homeopathic medicines in the Russian Federation and abroad are formed in accordance with regulatory acts, national and international rules and guidelines. Scientific literature is particularly important for justification of safety of homeopathic medicines. The purpose of this study was to determine the requirements and procedure for presenting justification of homeopathic medicines safety in the registration dossier in accordance with the documents of the Eurasian Economic Union and the European Union. According to the current Russian and foreign regulatory approaches the safety may be justified by scientific literature data on homeopathic use and by substantiation of the dosage in the case of medicines that have long experience of safe use and those that are authorized under a simplified procedure based on a dossier with a product instruction that does not establish indications for use. In both cases, there is no need to provide the results of preclinical or clinical studies of the drug. This approach reflects specific features of homeopathic medicines. An objective criterion of the safety of homeopathic medicines is the assessment of the dosage of active substances, taking into account the «first safe dilution» of homeopathic substances. A formal safety justification using registration data for similar drugs or additional information on the use of these pharmaceutical substances in homeopathy is also possible, but may be insufficient. The completeness and proper documentation of bibliographic data are the main criteria for an appropriate rationale for the safety of homeopathic products.

The quality and effectiveness of preclinical trials of medicines depend on compliance with the Good Laboratory Practice (GLP) principles. At the same time, the data of the World Health Organisation (WHO) and the analysis of the regulatory framework suggest that the reliability and reproducibility of the results of basic biomedical research are currently a very urgent problem in medicine development. Due to the exploratory nature of studies related to confirmation of scientific hypotheses, and the variety of methodological approaches used, strict GLP criteria cannot be applied to all types of pharmacological studies. According to international acts, GLP principles have the status of requirements and regulate the quality of preclinical safety studies as represented by well-standardised «batteries of tests» used in toxicological studies and safety pharmacology studies, but they do not apply to studies of primary pharmacodynamics which determine potential therapeutic efficacy of the medicinal product. Foreign regulators recommend applying GLP principles to secondary pharmacodynamics studies as well, especially if this type of research makes an important contribution to the safety assessment of medicines. Thus, studies of pharmacological activity of medicines, which are crucial in assessing the prospects of the candidate medicine at the preclinical stage, are mostly «unregulated studies», the results of which may be incorrect. The article discusses the system of regulation of pharmacological studies, including principles of planning and implementation of these studies, as set out in recommendations on Quality Practice in Basic Biomedical Research (QPBR). The application of QPBR principles ensures reliability and reproducibility of the results of preclinical pharmacological studies and increases their scientific and practical value in the development of new medicines.

The article dwells upon the results of comparative analysis of the Russian national requirements and EAEU regulations dealing with evaluation of preclinical pharmacological studies. It highlights historical aspects of elaboration of regulatory requirements and scientific and methodological recommendations for conducting and evaluating preclinical pharmacological studies. According to the EAEU Rules of registration and evaluation of medicinal products for human use, the Common Technical Document has to include information on primary pharmacodynamics, secondary pharmacodynamics, safety pharmacology studies, and pharmacodynamic drug interactions, which are subject to evaluation during examination of the preclinical study results. The national guideline on evaluation of medicines does not contain any clear indication of the subject of examination in primary and secondary pharmacodynamic studies, which can make it difficult to prepare a registration dossier in the format of a Common Technical Document. The article formulates basic approaches to expert evaluation of the results of preclinical studies of primary and secondary pharmacodynamics of medicines. It determines the basics of expert evaluation which covers methodological framework of the research, results of the research, characteristics of the safety profile, extrapolation of preclinical data, characteristics of risk factors and of the predictable clinical safety profile for patients.

The article analyses the regulatory and legal framework for medicines evaluation in the Russian Federation and abroad, as well as guidelines, scientific literature and practical experience to justify criteria for evaluation of efficacy and safety of homeopathic medicines. When selecting appropriate evaluation criteria the authors took into account specificity of homeopathic medicines composition and dosage form formulation, specific characteristics of pharmaceutical substances and therapeutic action, as well as known limitations on the use of standard test methods. The key criteria for homeopathic medicines evaluation are: compliance of the substance quality and the drug production technology with corresponding pharmacopoeial requirements, substantiation of the drug composition safety, and confirmation of the proposed efficacy and safety by the evidence-based pre-clinical and clinical programme.

The article substantiates approaches to evaluation of results obtained in preclinical safety pharmacology studies. It describes historical background for the development of regulatory requirements and methodological recommendations for performance of such studies, provides a classification of various types of safety pharmacology studies, lays down general requirements for examination of the main battery of tests as well as subsequent and additional tests, examines the aims and main tasks of such studies, and cites examples of tests. The authors define the main scope of expert evaluation which includes the methodological basis of studies, results of studies, characterisation of a medicine’s safety profile, interpretation of preclinical data, assessment of risk factors and an anticipated clinical safety profile for patients.