Currently, the issues of antimicrobial therapy and antimicrobial resistance are key both for medicine and for healthcare in general for a number of fundamental rea­sons pertaining not only to the health sector but also to social, economic, and even political spheres. The problem of antimicrobial resistance requires immediate and coordinated global action. This interview discusses the main strategies to ensure rational antimicrobial therapy and manage the associated risks in the current clinical setting with Roman S. Kozlov, Honoured Scientist of the Russian Federation, Rector of Smolensk State Medical University, Chief External Expert in Clinical Microbiology and Antimicrobial Resistance of the Ministry of Health of the Russian Federation, Head of the World Health Organisation Collaborating Centre for Capacity Building on Antimicrobial Resistance Surveillance and Research, Corresponding Member of the Russian Academy of Sciences, and Doctor of Medical Sciences.

INTRODUCTION. A rational approach to antibiotic selection is a key factor in the successful treatment of various infections, and it also reduces the risk of antimicrobial resistance. Under the current circumstances, it is particularly important to understand what criteria doctors and pharmacists consider when selecting antibiotics and what patients see as priorities. After all, it is often the patient-centred approach that determines both medication persistence and treatment effectiveness. Given that perceptions of the perfect antibiotic can vary greatly, it is important to summarise these perceptions and identify the key criteria that doctors, pharmacists, and the general public consider as priorities for antibiotic therapy (with treatment of lower respiratory tract infections as a case study).

AIM. This study aimed to identify the opinions of doctors, pharmacists, and the general public on selecting the perfect antibiotic and on the current state of antibiotic therapy for lower respiratory tract infections.

MATERIALS AND METHODS. This study included an opinion survey using questionnaires. The questionnaires were developed specifically for health professionals and antibiotic consumers. The sociological study involved 250 health professionals (doctors and pharmacists) and 150 respondents from the general public.

RESULTS. The majority of health professionals (55.6% of doctors and 53.7% of pharmacists) believe that antibiotics are “very often” prescribed for lower respiratory tract infections. Health professionals think that the main factors contributing to antimicrobial resistance are “unjustified prescription of antibiotics” (21.0% of doctors and 24.1% of pharmacists), “overly frequent courses of antibiotics” (17.2% of doctors and 21.5% of pharmacists), and “errors in antibiotic selection” (16.9% for both groups). Most doctors (93.7%) and pharmacists (83.0%) actively instruct patients in the proper use of antibiotics. When selecting the perfect antibiotic, health professionals and the public prioritise efficacy, safety, and tolerability. The most significant factors in selecting antibiotics for children include minimal risk of allergic reactions, convenience of dosing, and availability of dose calculation guidelines. Syrup is the most preferable paediatric dosage form for all groups of respondents. Only 42.2% of doctors claim that they always provide patients with a prescription for antibiotics, and 53.3% of pharmacists regularly encounter customers without a prescription.

CONCLUSIONS. This survey of doctors, pharmacists, and the public has identified cases of poor compliance with the regulations for dispensing and prescribing antibiotics on the part of doctors and cases of prescribing antibiotics without sound clinical justification, administering antibiotics without appropriate treatment-free intervals between courses, and making errors in antibiotic selection. Study mate­rials may inform the development of recommendations on antibiotic treatment of lower respiratory tract infections to be used as part of continuing professional training curricula for specialists dealing with medicines throughout the pharmaceutical product lifecycle.

INTRODUCTION. High rates of emergence and spread of antimicrobial resistan­ce (AMR) necessitate the rapid development of novel antibacterial medicinal products. The assessment of the microbial potential for AMR development under controlled conditions in vitro can save resources during drug development and marketing authorisation and contribute to creating the most effective medicinal products.

AIM. The aim was to determine the possibility of using the adaptive laboratory evolution (ALE) method to study the development of antimicrobial resistance.

DISCUSSION. A variety of methods can be used to investigate the mechanisms of AMR and the influence of medicinal products on the evolution of bacteria towards AMR. One of the options is the ALE method. ALE experiments are conducted under controlled conditions with prolonged exposure of microorganisms to an antibacterial agent. ALE experiments can include serial transfers of microorganisms to fresh liquid media or Petri dishes, as well as continuous cultivation of microorganisms in a chemostat. ALE protocols are used to develop resistance to different antibacterial agents and require meticulous control of the experimental conditions. To obtain reliable results in an experiment, it is necessary to identify parameters that may affect AMR development in microorganisms. These parameters include but are not limited to the concentration of the antibacterial agent, the number of consecutive passages, and the duration of incubation.

CONCLUSIONS. To achieve the necessary conditions for resistant microorganisms to form, it is essential to adhere strictly to ALE setup requirements, such as using antibacterial agents at subinhibitory or dynamically increasing concentrations (relative to the minimum inhibitory concentrations for the ancestral strain), performing a certain number of passages for ≥20 generations, and incubating cultures until the stationary phase. Despite the fact that ALE experiments are rather lengthy, these studies can reduce the potential waste of resources on developing new compounds that may have to be discontinued at the stage of production because of AMR development.

INTRODUCTION. Cephalosporins are injectable antibiotics, which are mainly free from excipients. Testing for impurities (degradation products) and the colour of solution can help evaluate degradation processes in cephalosporin active substances. Therefore, such testing is important for the quality control of cephalosporins.

AIM. This study aimed to evaluate the stability of cephalosporins in aqueous solutions in terms of impurities and the colour of solution and explore the relationship between these quality parameters.

MATERIALS AND METHODS. This study focused on cephalosporin active substances, including cefazolin, cefuroxime, ceftriaxone, and a combination of ceftriaxone and sulbactam (2:1). The colour intensity of aqueous solutions of these antibiotics was examined by visual comparison with reference standards and by spectrophotometry. The absorbance values of 10% cefazolin solution were measured at 430 nm at fixed intervals for 6 days, and those of 1.2% ceftriaxone and ceftriaxone–sulbactam solutions were determined at the maximum absorption wavelength of 450 nm for 11 days and 16 days, respectively. High-performance liquid chromatography (HPLC) was used to determine the content of related substances in solutions of cefazolin (10% and 0.25%), ceftriaxone (1.2% and 0.03%), and the ceftriaxone–sulbactam combination (1.2%, calculated as ceftriaxone). Ceftriaxone solutions were studied for 16 days, and cefuroxime solutions (10% and 0.1%) were studied for 2 days (48 hours). All the test solutions were stored at room temperature in natural light (away from direct sunlight).

RESULTS. During the test period, all the test solutions gradually acquired an intense yellow colour, and their absorbance and related substance content increased accordingly. Diluted solutions of cefazolin, ceftriaxone, and cefuroxime degraded significantly faster than the solutions of these antibiotics of a higher concentration. The experiment showed that the content of only one or two impurities increased during the first 24–96 hours of degradation, while the content of the remaining related substances changed insignificantly. Cefuroxime proved to be the least stable in aqueous solutions; the content of dezarbomoyl cefuroxime exceeded the limit specified by the regulatory requirements by 2.5 times after 24 hours of storage. The colour of 1.2% ceftriaxone deviated from the regulatory requirements after 24 hours, and the content of individual impurities exceeded the applicable limit for after 72 hours.

CONCLUSIONS. The study has shown that the stability of cephalosporins in aqueous solutions in terms of impurities and the colour of solution depends on the chemical structure of the substance, the concentration of the solution, and the duration of storage in natural light. A correlation has been demonstrated between the absorbance of cefazolin and ceftriaxone solutions and the content of individual impurities.

INTRODUCTION. The quality control of biotechnological medicinal products requires a range of biological assay procedures. The development of bioassays for potency determination is a complex process that should comply with the requirements set forth in regulatory standards. For adequate reproducibility, bioassays should be properly described in draft product specification files.

AIM. This study aimed to summarise the recommendations for developing in vitro bioassays for potency determination of monoclonal antibody preparations and for describing these bioassays in product specification files.

DISCUSSION. This article describes the Fab- and Fc-associated biological activi­ty mechanisms of monospecific and bispecific monoclonal antibodies. The article covers in vivo and in vitro methods used to study these mechanisms, with emphasis on the reporter gene assay. The article formulates the concept and analyses the components of a holistic analytical system that is necessary for bioassay development. A well-designed analytical procedure can minimise the influence of critical factors on the test results and reduce the risks of both random and systematic errors. This article presents an estimation of the significance of detailed description of critical procedure parameters in the draft product specification file for a monoclonal antibody.

CONCLUSIONS. A bioassay for the determination of potency should reflect the mecha­nism of action of the medicinal product and should provide the lowest possible variability and the highest possible ease of use. An adequate analytical procedure with appropriate analytical conditions can reduce the risk of obtaining invalid quality control results.

INTRODUCTION. A new ear drop composition based on European mistletoe (Viscum album L.) leaf soft extract was developed to meet the demand for cerumenolytic ear drops. The registration dossier for this medicinal product must include an analytical procedure for the quantitative analysis of the main active substance in V. album leaf soft extract (choline).

AIM. This study aimed to develop and validate an analytical procedure for the quan­titative determination of choline in cerumenolytic ear drops based on V. album leaf soft extract.

MATERIALS AND METHODS. The presence of nitrogenous bases was determined by paper chromatography. Munktell chromatography paper (grade FN7, size 4×25 cm) was used as the stationary phase. The mobile phase consisted of the following solvent systems: n-butanol — ethanol — acetic acid — water (8:2:1:3), n-butanol — acetic acid — water (4:1:5), and acetic acid — water (15:85). The colour development reagent was iodine vapour. The spectrophotometric determination of nitrogenous bases was conducted using an SF-102 spectrophotometer and a detector at a wavelength of 400±2 nm in the presence of ammonium reineckate (Reinecke’s salt). The analytical procedure for the quantitative determination of choline ethers was validated for specificity, linearity, accuracy, and precision.

RESULTS. This study developed and validated a spectrophotometric analytical procedure for the quantitative determination of choline ethers calculated as choline in cerumenolytic ear drops based on V. album leaf soft extract in the presence of Reinecke’s salt. The analytical procedure identified choline and its esters (acetylcholine, acetylcholine iodide, and benzoylcholine) in the analysed ear drops. The content of choline esters calculated as choline was 0.710±0.018%.

CONCLUSIONS. The spectrophotometric analytical procedure for the quantitative determination of choline ethers in the presence of Reinecke’s salt can be recommended for the quality control of cerumenolytic ear drops based on V. album leaf soft extract.

INTRODUCTION. The Russian Federation has decided to restore the system of compounding pharmacies as an element of the critical national healthcare infrastructure and pharmaceutical supply chain. To improve Russian regulatory practices, develop novel advanced approaches to pharmacy compounding and quality control, and implement these approaches, it is necessary to study relevant good compounding practices applied in healthcare systems of other countries.

AIM. This study aimed to analyse the German experience in the organisation and regulation of pharmaceutical compounding to suggest recommendations for the development and implementation of Russian guidelines on good compounding and dispensing practices.

DISCUSSION. This work continues a comprehensive study that delves into the current provisions of German legislation governing the system of good compounding practices. This article examines the differences between approaches to compounding by medical and pharmaceutical specialists. According to the findings, compounding by medical specialists is guided by the “free practice of medicine” principle and is subject to minimal regulatory oversight. All pharmacy organisations operate as compounding pharmacies, thereby enhancing the physical accessibility of compounded medicinal products to the population. The authors highlight the features of a process-based quality assurance system encompassing production process controls and quality control methods for compounded medicinal products. Additionally, the authors discuss the applicability of rapid test methods to compounding. In accordance with the German concept of good pharmacy practices, a compounding pharmacy may use the available validation, qualification, and verification tools in the pharmaceutical development of compounded medicinal products and may outsource its internal quality control function. Using the concept of risk ranking, compounding pharmacies may design their own sampling programmes. The article describes approaches to and requirements for organising the evaluation of compounding prescriptions. In Germany, compounding pharmacies may independently assign shelf lives to the compounded medicinal products they produce.

CONCLUSIONS. Some German solutions are of considerable practical importance and are applicable to the development and implementation of Russian guidelines on good compounding and dispensing practices. In particular, pharmacy organisations may outsource the quality control of their compounded medicinal products. Additionally, pharmacies can conduct the full-scale pharmaceutical development of compounding technologies and quality control methods (including rapid test methods) using the validation, qualification, and verification tools available to drug manufacturers. Moreover, pharmacy organisations may independently assign shelf lives to the compounded medicinal products they produce. Finally, pharmacy orga­nisations may design their individual sampling programmes.

INTRODUCTION. Functional gastrointestinal disorders (FGIDs) are a heterogeneous group of disorders characterised by non-specific clinical signs that may occur in various diseases of the digestive system. Currently, there are no guidelines for conducting clinical trials of medicinal products for FGIDs in the Russian Federation. It is, therefore, essential to develop such guidelines taking into account the current requirements for marketing authorisation in the Eurasian Economic Union (EAEU).

AIM. This study aimed to provide a systematic overview of international approaches to clinical trials of medicinal products for FGIDs, which will inform further development of a guideline for conducting these clinical trials in the Russian Federation.

DISCUSSION. The gold standard for assessing the safety and efficacy of pharmacotherapy is a randomised, double-blind, parallel-group, placebo-controlled trial. The design of a clinical trial depends on a number of factors, including the type and severity of the FGID, the demographics of the target population, the selected endpoints, and the presence (or absence) of specific symptom combinations and biomarkers. To plan a clinical trial that meets the principles of evidence-based medicine, the Rome IV criteria should be used consistently at all stages of treatment strategy development and assessment.

CONCLUSIONS. Following the described fundamental principles for the development of clinical trial programmes for medicinal products for FGIDs will ensure that clinical trials are planned and conducted in full compliance with international approaches and ethical standards. The development of a Russian guideline for planning clinical trials of the safety and efficacy of medicinal products for FGID management will facilitate selecting the optimum treatment method from a wide spectrum of available treatments.

INTRODUCTION. Survival analysis is an important biostatistics method used in clinical trials to confirm the long-term efficacy and safety of medicinal products. The significance of this method lies in the possibility to extrapolate the conclusion regarding the benefits of a medical intervention drawn from a short-term clinical trial to a longer period and adjust dosages and treatment regimens accordingly. However, comprehensive methodological recommendations for planning survival analyses are currently lacking.

AIM. This study aimed to systematise the requirements for sample size calculation in event-based study designs.

DISCUSSION. This article presents methods for calculating the number of subjects required for survival analysis in event-driven studies with outcome collection and estimation under censoring conditions. The authors discuss Bayesian probabilistic models for estimating survival parameters, such as the time to an event, the risk of an event, and the cumulative survival rate, as key variables for determining the sample size for a study. The article presents a theoretical framework for event risk analysis in survival study designs. The authors describe hypotheses and sta­tistical models for calculating sample sizes and determining survival parameter thresholds in group sequential designs for event risk studies.

CONCLUSIONS. The statistical models presented can be used to design studies aimed at estimating the time to an expected event and the cumulative risk during treatment and following medicinal product administration.

INTRODUCTION. Current scientific knowledge in the field of molecular biology and the associated manufacturing and technical capabilities enable the development of radiopharmaceuticals (RPs) with high specificity to the target organs, tissues, and receptors. The development of novel RPs requires mandatory clinical trials. However, at the moment, the Russian Federation and the Eurasian Economic Union (EAEU) lack documented guidance for drafting application dossiers for obtaining authorisation for clinical trials of RPs. There is a need for guidelines that will set forth recommendations for planning comprehensive clinical development programmes and regulate data submission requirements for clinical trials of various types of RPs.

AIM. This study aimed to explore whether the methodological approaches outlined in international regulatory documents can be used to inform the development of a Russian guideline for the conduct of clinical trials of RPs.

DISCUSSION. The authors conducted an extensive analysis of the Russian and EAEU laws and regulations and the guidelines by regulatory agencies in Europe (European Medicines Agency, Swissmedic), the US, and Canada that included provisions for planning and conducting clinical trials of RPs. This analysis identified the key considerations defining the clinical development programme for an RP (including its innovation level and administration route). This article describes the main phases of clinical trials and defines the phase-specific aspects of planning clinical trials of PRs. These aspects include the selection of the trial population, endpoints, design, and duration and considerations for special patient populations. The article summarises the requirements for the content of the application dossiers submitted to regulatory authorities to obtain authorisation to conduct clinical trials of RPs. The article outlines typical nonconformities and errors in application dossiers identified during the assessment of RP clinical trial protocols submitted to the Scientific Centre for Expert Evaluation of Medicinal Products of the Ministry of Health of the Russian Federation in 2020–2024.

CONCLUSIONS. This comprehensive analysis of the documents regulating the leading regulators’ approaches supplemented with the critical assessment of the Russian experience can serve as a basis for the development of clinical programmes for both novel diagnostic/therapeutic RPs and well-characterised compounds. The considerations presented in the article may be used by experts reviewing clinical trial results and by RP developers.