Development of guidelines on good manufacturing of biomedical cell products

The article presents the essence of draft of the Guidance of good manufacturing practices of biomedical cell products (BMCP) (GMP/GTP guideline) harmonized with the international requirements, which contains the basic quality and safety standards of clinical application of these products. These regulations prescribe the requirements for institutions engaged in one or more stages of BMCP production and allow to avoid any risk of contamination of cells, tissues and finished product. The aim of this work is to develop a methodology for BMCPs' quality assurance framework. Materials and methods. The main subjects of research are national and international laws and regulations, publications on quality assurance systems of cell products, problems of BMCP manufacturing and validation. Results. The draft Guidance of good manufacturing practices of BMCP (GMP/GTP guideline), including specific requirements to donor determination, biomaterial sampling and its transportation to the manufacture, to risk management system, traceability system, to processing, definition of minimally manipulated BMCP, requirements to incoming control, continuous in-process control and control of finished BMCP, to pharmacovigilance system were developed. Specific features of the manufacture of test products for non-clinical and clinical studies are described. Assessment elements for certification prior to release of each batch of test BMCP were clarified. Recommendations on the introduction of a product coding system according to ISBT 128 Standard are given in this work

Risks of clinical trial protocol amendments according to duration of the trial

Background. No clinical trial could be initiated and conducted without appropriate clinical trial protocol. Any change in information relating to patients’ safety and health during the trial must be recorded and approved by a form of amendment to the clinical trial protocol, which is a time-consuming and financially expensive process for the Sponsors of these studies.Goal. To analyze the probability of releasing of clinical trials protocols amendments and to determine the most "pregnable" period for their occurrence in the course of the trials.Materials and Methods. The results of clinical trial protocols analysis are presented, which were approved by Russian Health Authorities between three years from 2017 to 2019 inclusive. In total, 20 protocols and 39 amendments were analyzed. Results. In the first year of the study, 21 amendments were issued, representing slightly more than half (54%) of the total number of amendments. During the second year, 12 amendments were issued, (31%). For the third year of the trial, only 3 amendments (7%) were made and for the fourth — 4, which is 8% of the total.Conclusion. The largest number of protocol amendments came out at first two years of clinical trial. Thus, they are the most "dangerous" years in the life of a clinical study in connection with the examination of developed protocol in real life. These first two years show how carefully the protocol was designed, how it meets the requirements of regulatory authorities, criteria and recommendations of professional associations, how feasible and effective the various criteria and procedures are

Impact of COVID-19 on clinical trials protocol amendments

The COVID-19 pandemic situation had a great impact on all spheres of people’s lives. It also affected clinical trials as Sponsors, sites and investigators faced a number of problems, such as systematic IMP taking, adherence to protocol visits, efficacy evaluations, laboratory procedures, and analyse

Transient receptor potential Ankyrin 1: structure, function and ligands

The aim of this study is to search and generalize information about structural features and molecular determinants, mechanisms of activation, action and modulation of TRPA1 as a universal pain and inflammation sensor, as well as the nature of activators and antagonists of this target and their therapeutic potentia

Point-of-care diagnostic tests for detecting sars-cov-2 antibodies: A systematic review and meta-analysis of real-world data

SARS-CoV-2 is responsible for a highly contagious infection, known as COVID-19. SARS-CoV-2 was discovered in late December 2019 and, since then, has become a global pandemic. Timely and accurate COVID-19 laboratory testing is an essential step in the management of the COVID-19 outbreak. To date, assays based on the reverse-transcription polymerase chain reaction (RT-PCR) in respiratory samples are the gold standard for COVID-19 diagnosis. Unfortunately, RT-PCR has several practical limitations. Consequently, alternative diagnostic methods are urgently required, both for alleviating the pressure on laboratories and healthcare facilities and for expanding testing capacity to enable large-scale screening and ensure a timely therapeutic intervention. To date, few studies have been conducted concerning the potential utilization of rapid testing for COVID-19, with some conflicting results. Therefore, the present systematic review and meta-analysis was undertaken to explore the feasibility of rapid diagnostic tests in the management of the COVID-19 outbreak. Based on ten studies, we computed a pooled sensitivity of 64.8% (95%CI 54.5-74.0), and specificity of 98.0% (95%CI 95.8-99.0), with high heterogeneity and risk of reporting bias. We can conclude that: (1) rapid diagnostic tests for COVID-19 are necessary, but should be adequately sensitive and specific; (2) few studies have been carried out to date; (3) the studies included are characterized by low numbers and low sample power, and (4) in light of these results, the use of available tests is currently questionable for clinical purposes and cannot substitute other more reliable molecular tests, such as assays based on RT-PCR

Comparative study of MRI biomarkers in the substantia nigra to discriminate idiopathic Parkinson disease

BACKGROUND AND PURPOSE: Several new MR imaging techniques have shown promising results in patients with Parkinson disease; however, the comparative diagnostic values of these measures at the individual level remain unclear. Our aim was to compare the diagnostic value of MR imaging biomarkers of substantia nigra damage for distinguishing patients with Parkinson disease from healthy volunteers. MATERIALS AND METHODS: Thirty-six patients and 20 healthy volunteers were prospectively included. The MR imaging protocol at 3T included 3D T2-weighted and T1-weighted neuromelanin-sensitive images, diffusion tensor images, and R2* mapping. T2* high-resolution images were also acquired at 7T to evaluate the dorsal nigral hyperintensity sign. Quantitative analysis was performed using ROIs in the substantia nigra drawn manually around the area of high signal intensity on neuromelanin-sensitive images and T2-weighted images. Visual analysis of the substantia nigra neuromelanin-sensitive signal intensity and the dorsolateral nigral hyperintensity on T2* images was performed. RESULTS: There was a significant decrease in the neuromelanin-sensitive volume and signal intensity in patients with Parkinson disease. There was also a significant decrease in fractional anisotropy and an increase in mean, axial, and radial diffusivity in the neuromelanin-sensitive substantia nigra at 3T and a decrease in substantia nigra volume on T2* images. The combination of substantia nigra volume, signal intensity, and fractional anisotropy in the neuromelanin-sensitive substantia nigra allowed excellent diagnostic accuracy (0.93). Visual assessment of both substantia nigra dorsolateral hyperintensity and neuromelanin-sensitive images had good diagnostic accuracy (0.91 and 0.86, respectively). CONCLUSIONS: The combination of neuromelanin signal and volume changes with fractional anisotropy measurements in the substantia nigra showed excellent diagnostic accuracy. Moreover, the high diagnostic accuracy of visual assessment of substantia nigra changes using dorsolateral hyperintensity analysis or neuromelanin-sensitive signal changes indicates that these techniques are promising for clinical practice

Spatiotemporal changes in substantia nigra neuromelanin content in Parkinson’s disease

This study aimed to investigate the spatiotemporal changes in neuromelanin-sensitive MRI signal in the substantia nigra and their relation to clinical scores of disease severity in patients with early or progressing Parkinson’s disease and patients with idiopathic rapid eye movement sleep behaviour disorder (iRBD) exempt of Parkinsonian signs compared to healthy control subjects. Longitudinal T1-weighted anatomical and neuromelanin-sensitive MRI was performed in two cohorts, including patients with iRBD, patients with early or progressing Parkinson’s disease, and control subjects. Based on the aligned substantia nigra segmentations using a study-specific brain anatomical template, parametric maps of the probability of a voxel belonging to the substantia nigra were calculated for patients with various degrees of disease severity and controls. For each voxel in the substantia nigra, probability map of controls, correlations between signal-to-noise ratios on neuromelanin-sensitive MRI in patients with iRBD and Parkinson’s disease and clinical scores of motor disability, cognition and mood/behaviour were calculated. Our results showed that in patients, compared to the healthy control subjects, the volume of the substantia nigra was progressively reduced for increasing disease severity. The neuromelanin signal changes appeared to start in the posterolateral motor areas of the substantia nigra and then progressed to more medial areas of this region. The ratio between the volume of the substantia nigra in patients with Parkinson’s disease relative to the controls was best fitted by a mono-exponential decay. Based on this model, the pre-symptomatic phase of the disease started at 5.3 years before disease diagnosis, and 23.1% of the substantia nigra volume was lost at the time of diagnosis, which was in line with previous findings using post-mortem histology of the human substantia nigra and radiotracer studies of the human striatum. Voxel-wise patterns of correlation between neuromelanin-sensitive MRI signal-to-noise ratio and motor, cognitive and mood/behavioural clinical scores were localized in distinct regions of the substantia nigra. This localization reflected the functional organization of the nigrostriatal system observed in histological and electrophysiological studies in non-human primates (motor, cognitive and mood/behavioural domains). In conclusion, neuromelanin-sensitive MRI enabled us to assess voxel-wise modifications of substantia nigra’s morphology in vivo in humans, including healthy controls, patients with iRBD and patients with Parkinson’s disease, and identify their correlation with nigral function across all motor, cognitive and behavioural domains. This insight could help assess disease progression in drug trials of disease modification

Трансдермальные терапевтические системы доставки лекарственных средств

A review of existing transdermal therapeutic systems of drug delivery is presented. The advantages and disadvantages of these systems and t he dominating ways of development and creation of most advanced forms of medicines are shown.Представлен обзор существующих трансдермальных терапевтических систем доставки лекарственных веществ, отмечены их достоинства и недостатки, освещены преимущественные пути развития и создания наиболее перспективных форм лекарственных средств

Review of the Certification Procedure for Qualified Persons of Manufacturers of Medicines for Human Use in Russia

Scientific relevance. In December 2020, the Russian Federation adopted the Eurasian Economic Union (EAEU) requirements. This has significantly changed the certification procedure for qualified persons (QPs) of manufacturers of medicinal products for human use in the Russian Federation. To accommodate these changes, the Russian regulatory framework needs further improvement.Aim. This study aimed to review the changes made to the mechanism of state regulation of medicines and to evaluate the impact on the pharmaceutical industry two years after the adoption of the current QP certification procedure.Discussion. This review compares two QP certification procedures established by Order No. 7n of the Ministry of Health of the Russian Federation dated 12 January 2021. The first is an abbreviated one for QPs certified under the previous procedure, and the second is an initial one for QPs being certified for the first time, having an expired certificate, or wishing to extend their professional qualification profiles. The article illustrates common mistakes made by certification applicants when preparing their documents. Furthermore, the authors describe the most prevalent knowledge gaps identified by testing. The abbreviated certification procedure ensured a sufficiently smooth transition to the EAEU requirements. For example, by 1 February 2023, 506 QPs were recertified for the next five-year period according to this procedure. This accounts for slightly more than half of all QPs certified in the Russian Federation according to the previous requirements. The total number of QPs certified according to the EAEU requirements in Russia in 2021–2022 is approximately 1.5 times higher than the number of QPs certified during the same period in 2014–2015.Conclusions. The updated procedure for QP certification has noticeably changed the occupational group of QPs formed in the Russian Federation in the last decade. The implementation of the new QP certification procedure has revealed several procedural issues that require additional explanation and clarification by the Ministry of Health of the Russian Federation