Development Of Innovative Medicines Research Articles

In silico evaluation of the pharmacodynamic component of the interaction of S-alkyl derivatives of 5-methyl-4-(p-tolyl)-1,2,4-triazole-3-thiol with some biological targets

Derivatives of 1,2,4-triazole open wide opportunities for modern and progressive scientists in the development of innovative medicines. These compounds are known for their variability and structural flexibility, which allows scientists to experiment and create new molecules with unique properties. The use of 1,2,4-triazole derivatives in the creation of drugs is based on their ability to interact with biological systems and molecular targets. These compounds can be aimed at regulating physiological processes, reducing manifestations of pathological conditions or enhancing necessary biological reactions. Directed modification of the structure of 1,2,4-triazole derivatives allows to create biologically active compounds with improved properties. The aim of the work was to study in silico and to evaluate the possible interaction of a virtual series of S-alkyl derivatives of 5-methyl-4-(p-tolyl)-1,2,4-triazole-3-thiol with some enzyme systems. Materials and methods. A computer method (molecular docking) for predicting and evaluating the interaction between a ligand molecule and a target protein structure. Ligand preparation was performed using MarvinSketch 6.3.0, Hyper Chem 8, and AutoDockTools-1.5.6 programs. Enzyme preparation involved the use of Discovery Studio 4.0 and AutoDockTools-1.5.6 software packages. Direct molecular docking was performed using the Vina program. Results. A virtual series of S-alkyl derivatives of 5-methyl-4-(p-tolyl)-1,2,4-triazole-3-thiol with the potential possibility of creating a biologically active substance has been constructed. Using the Vina software tool, the nature and number of amino acid residues of the active centers of model enzymes, with which the proposed ligands coordinate and bind, were determined. According to the results of docking studies, the predicted affinity for lanosterol-14α-demethylase was determined. The effect on the receptor tyrosine kinase of anaplastic lymphoma is somewhat inferior in terms of qualitative and quantitative indicators. Conclusions. Using the method of molecular docking, it was established that S-alkyl derivatives of 5-methyl-4-(p-tolyl)-1,2,4-triazole-3-thiol have a fairly significant potential for the manifestation of antifungal activity, which justifies the further synthesis of these compounds and more in-depth study of fungistatic and fungicidal properties. Docking results for anaplastic lymphoma kinase show little promise in the development of anticancer agents.

Poland - National regulation on processing data for scientific research purposes and biobanking activities

Biobanks raise great hopes for future research that can help understand many diseases and find ways to treat them. The purpose of the article is to study the legislative acts regulating the activities of biobanks in Poland and to formulate recommendations for improving the legal regulation of biobanking. For the purpose, tasks, object, and subject of research, both general scientific and special methods of scientific knowledge were used in the work. General scientific methods (dialectical; system analysis; formal-logical) are fundamental legal techniques, and means of research. To improve the current legislation of Poland, the following can be proposed. Develop a legal framework that regulates the legality of obtaining samples of human biological materials (both normal and pathologically altered) for submission to the biobank in Poland. Regulate at the legislative level the requirements regarding the organizational and legal form of the creation of a biobank, the legal basis of its functioning, the form of ownership, and financing. Thus, the creation of an effective system of biobanks in Poland with systematic collections of biological samples obtained from people with various diseases, their storage in appropriate conditions, the development of internal documentation and standard operating procedures, taking into account both the ethical and legal components, is of key importance for the formation and development of domestic science, development of innovative medicines, methods of diagnosis and monitoring of diseases.

World practice of providing scientific advice on the development and authorisation of innovative medicines

Current challenges to healthcare, i.e. the emergence of new diseases, lack of therapies for known diseases and life-threatening conditions, identification of patients who do not respond to standard treatment, on the one hand, and the evolution of scientific understanding of disease processes, medicines, therapies, causes of treatment failures, and implementation in clinical practice of innovations related to molecular biology and genetic engineering, on the other hand, create conditions and opportunities for the development of innovative medicinal products. A relatively new class of medicines is based on human cells and tissues (the term used in Russian legislation is biomedical cell products, BCP). However, the inability to accurately predict the efficacy and financial rewards of such medicines for pharmaceutical companies, as well as significant labour and financial costs associated with their development and clinical use, hinder their entry into the market. The aim of the study was to analyse the foreign regulatory setting for the development and launch of human cell- and tissue-based products, as well as approaches of foreign regulatory authorities to scientific advice, which can be drawn upon by the Russian expert authority when providing advice to BCP developers. The paper summarises the results of analysis of regulations establishing the procedure for providing scientific advice by EU, USA, and Russian regulatory authorities, and analyses the advice provided for the human cell- and tissue-based products which are now authorised in the EU and USA. The analysis of advice provided by foreign regulatory authorities shows that the largest number of consultations were given for medicinal products based on genetically modified cells for the treatment of cancer and genetic diseases. The questions were mainly related to the contents of specifications for finished pharmaceutical products, safety evaluation, curtailing of preclinical studies due to the lack of relevant animal/disease models, the number of subjects and efficacy endpoints in clinical studies, assessment of the appearance of replication-competent retroviruses.

The legal status of participants who create medicines in the national innovation system

Formulation of the problem. Carrying out scientific research in the field of creating innovative medicines is the key to the competitiveness of pharmaceutical enterprises in the internal Ukrainian and world markets. Proper legal regulation of the legal status of business entities and scientific institutions that create medicines should become a guarantee of state support for scientific research in this area. Recent research on the topic. The scientific works of V.M. Pashkova, I.S. Voronina, M.V. Bunyak and other researchers are devoted to certain problems of innovative activity in the sphere of medicine circulation. At the same time, the problems of the legal status of participants in the national innovation system who create new medicines have not found their coverage in the scientific literature. The purpose of this research is to determine the legal status of participants in the national innovation system, who create medicines. Article’s main body. The scientific research is devoted to the determination of the legal status of the participants of the national innovation system who create medicines. Legislative and by-laws, statistical information posted on the official websites of authorities, publications of researchers who studied innovative activities in the field of medicine circulation were studied. It is stated that the development of innovative medicines can be carried out by research institutes, institutions of higher education and pharmaceutical manufacturing enterprises. Medicines productions are created in the organizational and legal form of private and state enterprises, business entities. Research institutes and institutions of higher education have legal form of organization. These institutions are subordinate to either the Ministry of Education and Science, or the Ministry of Health Protection, or the National Academy of Medical Sciences, or the State Service for Medicines and Drug Control of Ukraine. Among the conditions for obtaining a license for the medication production there is no requirement for a laboratory to create new medicines at the enterprise. Requirements for such a laboratory are not provided for in legislative and bylaws. Conclusions and prospects for the development. The author proposes definitions of “medicine developer” and “innovative pharmaceutical organization”. The features of the pharmaceutical enterprise innovativeness, in our opinion, are the presence of a scientific department in the structure of the enterprise and the registration of an innovative project by this enterprise in the prescribed manner. The consolidation of these definitions in the legislation of Ukraine may be important for obtaining state support for scientific research on the new medicines creation.

Advances in translational orthopaedic research with species-specific multipotent mesenchymal stromal cells derived from the umbilical cord.

Compliance with current regulations for the development of innovative medicines require the testing of candidate therapies in relevant translational animal models prior to human use. This poses a great challenge when the drug is composed of cells, not only because of the living nature of the active ingredient but also due to its human origin, which can subsequently lead to a xenogeneic response in the animals. Although immunosuppression is a plausible solution, this is not suitable for large animals and may also influence the results of the study by altering mechanisms of action that are, in fact, poorly understood. For this reason, a number of procedures have been developed to isolate homologous species-specific cell types to address preclinical pharmacodynamics, pharmacokinetics and toxicology. In this work, we present and discuss advances in the methodologies for derivation of multipotent Mesenchymal Stromal Cells derived from the umbilical cord, in general, and Wharton's jelly, in particular, from medium to large animals of interest in orthopaedics research, as well as current and potential applications in studies addressing proof of concept and preclinical regulatory aspects.

Научно-практический подход к оптимизации затрат на разработку и продвижение лекарственных препаратов

In order to identify promising strategic development possibilities for the pharmaceutical industry in the Russian Federation, a pilot study was conducted, which has analyzed the main trends in the development of innovative medicines. As a result of the content analysis of available sources of scientific literature, the characteristics of options used in the world practice for increasing the innovative activity of individual subjects and the pharmaceutical market as a whole are presented. Possible reserves for the further development of the innovative component of the pharmaceutical market within the framework of the concept of personalized medicine according to the P4 principle (predictive - personalized - preventive - participatory) are identified and structured.
 The results of use by individual pharmaceutical companies of scientifically and practically justified approaches to optimizing the costs of development and promoting drugs are presented. The advantages and real prospects of a generally accepted method to reduce the cost of development by «expanding the pharmacological effect» (label expansion) of already existing drugs with a known safety profile in the world practice are shown. A scientific generalization and structuring of the goals and results of the post-registration phase of clinical trials to expand the pharmacological action of a number of drugs already existed at the market have been carried out.

Strategic Shift of Statistical Review on Data Quality Assessment for New Drug Applications in China.

Data quality is critical for clinical trials to obtain robust conclusions about drug safety and efficacy evaluation. Effective data quality evaluation has been one of the major obstacles to new drug approvals in China, which hinders innovation in drug discovery and development ultimately. To improve the data quality submitted for regulatory drug approval, the China Food and Drug Administration (CFDA) has issued serial official announcements and industry guidelines regarding improvement of the clinical trial data integrity and quality since 2015. These announcements and follow-up measures are shaping up the entire pharmaceutical industry in China. While data quality is being strongly emphasized more than ever at the trial conduction phase, it is still an open question about how to assess data quality effectively at the review stage. Thus, this article describes the authors' standpoints to assess the quality and integrity of submitted clinical data via statistical review methods including advanced risk-based approaches, which may bring significant impact to new drug applications and motivate sustainable development of innovative medicines in China.

A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery.

Drug-induced nephrotoxicity is a major concern in the clinic and hampers the use of available treatments as well as the development of innovative medicines. It is typically discovered late during drug development, which reflects a lack of in vitro nephrotoxicity assays available that can be employed readily in early drug discovery, to identify and hence steer away from the risk. Here, we report the development of a high content screening assay in ciPTEC-OAT1, a proximal tubular cell line that expresses several relevant renal transporters, using five fluorescent dyes to quantify cell health parameters. We used a validation set of 62 drugs, tested across a relevant concentration range compared to their exposure in humans, to develop a model that integrates multi-parametric data and drug exposure information, which identified most proximal tubular toxic drugs tested (sensitivity 75%) without any false positives (specificity 100%). Due to the relatively high throughput (straight-forward assay protocol, 96-well format, cost-effective) the assay is compatible with the needs in the early drug discovery setting to enable identification, quantification and subsequent mitigation of the risk for nephrotoxicity.

The European Innovative Medicines Initiative: Progress to Date.

The Innovative Medicines Initiative is a public–private partnership between the European Union and the pharmaceuticals industry that was established in 2008, with an overall budget of €5.3 billion from 2008 until 2024. The objective of the initiative is to boost pharmaceutical innovation in Europe and speed up the development of innovative medicines, vaccines and medical technologies, in particular in areas with high unmet needs. This article discusses the objectives of the initiative, its governance and main results and impact. The initiative has proved to be a unique platform for multi-stakeholder collaborations across Europe. It has contributed to the acceleration of the development process for medicines, from drug discovery to clinical development. The initiative has made important steps towards accessing and using real-world evidence for pharmaceutical research and development, and for healthcare decision-making. Several projects have contributed to a better understanding of the causes of diseases, and some are already delivering results, such as a vaccine against Ebola virus. The initiative has also significantly contributed to building capacity and resources for open use by the broader research and innovation community.Electronic supplementary materialThe online version of this article (10.1007/s40290-018-0241-y) contains supplementary material, which is available to authorized users.

Main changes in European Clinical Trials Regulation (No 536/2014).

The new Regulation (EU) No. 536/2014 for clinical trials of medicinal products for human is part of a European regulatory framework in which the European Commission has wished to give a strong impetus to scientific research and industrial progress. It is a new regulation that fills a series of regulatory gaps in the Clinical Trials through the creation of a uniform framework for the authorization of clinical trials by all interested Member States with a single assessment of the results. The Regulation thus facilitates cross-border cooperation to make the clinical tests wider and encourage the development of special treatments, for example for rare diseases, but above all streamlines the rules on clinical trials across European Union (EU), introducing simplified rules for experimentation so-called 'low level of intervention', on which much has been discussed and still arouses concern, providing for authorized medicines or used off-label in the presence of scientific evidence published on efficacy and safety and to benefit from they will be mainly the pediatric and oncological therapeutic areas. The applications and any communication will be submitted paperlessly via a new electronic EU portal. The complex processing procedures and shorter time limits are to be stressed in comparison to the previously valid regulations. This is a major challenge for all stakeholders, but on the other hand it should contribute to the future role of the EU in the development of innovative medicines.

Navigating tissue chips from development to dissemination: A pharmaceutical industry perspective.

Tissue chips are poised to deliver a paradigm shift in drug discovery. By emulating human physiology, these chips have the potential to increase the predictive power of preclinical modeling, which in turn will move the pharmaceutical industry closer to its aspiration of clinically relevant and ultimately animal-free drug discovery. Despite the tremendous science and innovation invested in these tissue chips, significant challenges remain to be addressed to enable their routine adoption into the industrial laboratory. This article describes the main steps that need to be taken and highlights key considerations in order to transform tissue chip technology from the hands of the innovators into those of the industrial scientists. Written by scientists from 13 pharmaceutical companies and partners at the National Institutes of Health, this article uniquely captures a consensus view on the progression strategy to facilitate and accelerate the adoption of this valuable technology. It concludes that success will be delivered by a partnership approach as well as a deep understanding of the context within which these chips will actually be used. Impact statement The rapid pace of scientific innovation in the tissue chip (TC) field requires a cohesive partnership between innovators and end users. Near term uptake of these human-relevant platforms will fill gaps in current capabilities for assessing important properties of disposition, efficacy and safety liabilities. Similarly, these platforms could support mechanistic studies which aim to resolve challenges later in development (e.g. assessing the human relevance of a liability identified in animal studies). Building confidence that novel capabilities of TCs can address real world challenges while they themselves are being developed will accelerate their application in the discovery and development of innovative medicines. This article outlines a strategic roadmap to unite innovators and end users thus making implementation smooth and rapid. With the collective contributions from multiple international pharmaceutical companies and partners at National Institutes of Health, this article should serve as an invaluable resource to the multi-disciplinary field of TC development.

Can pharmaceutical co-crystals provide an opportunity to modify the biological properties of drugs?

Poorly soluble and/or permeable molecules jeopardize the discovery and development of innovative medicines. Pharmaceutical co-crystals, formed by an active pharmaceutical substance (API) and a co-crystal former, can show enhanced dissolution and permeation values compared with those of the parent crystalline pure phases. It is currently assumed that co-crystallization with pharmaceutical excipients does not affect the pharmacological activity of an API or, indeed, might even improve physical properties such as solubility and permeability. However, as we highlight here, the biological behavior of co-crystals can differ drastically with respect to that of their parent physical mixtures.

Development of Innovative Medicines for European Patients and Impact of Brexit

European patients may benefit from innovative medicines only at the end of a complex process with a sequence of positive decisions on different levels by different stakeholders. The decision of the industry to invest in a usually global clinical development must be followed by a European marketing authorization decision and a mostly national decision on price and reimbursement until finally patients and their physicians can make an individual treatment decision. Development strategies must consider the evolution of scientific and procedural requirements. Current trends are characterized by an enhanced cooperation of regulators and health technology assessment-bodies. The increasing availability of innovative personalized or precision medicines is reflected in the new procedural tools like European Medicines Agency’s priority medicines scheme and adaptive pathways concept. The UK decision to leave the EU will have consequences for their contribution to the European regulatory and health technology assessment network. Current strategies for the successful development of innovative medicines may need adjustments to address both scientific and political changes.

Affordable innovation: future directions in pharmaceutical policy

In 2009, Jayadev and Stiglitz [1] proposed ‘two ideas’ to increase innovation and reduce pharmaceutical costs and prices. These were the use of value-based pricing and promoting public funding of clinical trials. Since then, NICE has tried and not yet succeeded to introduce value-based pricing, Persson and Jonsson [2] suggest that international reference pricing should cease, Gilead has made billions on the basis of exorbitant pricing of new products for hepatitis C, and prices for new products for cancer are causing concern even in the US [3]. At the same time, there has been considerable work on how to promote research and development to meet health needs in developing countries [4], the reported cost of drug development seems to continue to increase [5], the structure of the multinational industry has changed significantly [6], there are major area of market failure such as antibiotics, and investment in public-private partnerships to promote innovation continues to grow. Given this complex landscape, this abstract briefly reviews the current ideas and strategies to promote innovation in pharmaceutical development. It provides a review of some of the issues about pricing and affordability of new medicines, and some options for ensuring that innovation is affordable. These options are likely to require some significant changes in our current approaches to negotiating pharmaceutical prices with suppliers, increased global and regional collaboration as well as increased transparency about clinical effects that are relevant to patients, costs of research and development and explicit consideration of willingness to pay by different countries. The problem of declining innovation in the pharmaceutical industry has been well described [6]. Trouiller et al. summarised the problem in 2002 [7], showing how few molecules had been approved by the FDA that were of relevance to neglected tropical diseases. The Priority Medicines for Europe and the World Report in 2004 [8] was one response, to identify priority products for potential development by European pharma. The regulatory framework for orphan drugs in both the USA and Europe was another mechanism [9] and similarly, the push for paediatric medicines tried to use incentives (patent protection) as well as sanctions to encourage needed product development. In 2012, the report [4] by the Consultative Expert Working Group on Research and Development identified a group of proposals that they considered most likely to promote innovation in research for products relevant to low and middle income countries. These were: a ‘Global Framework’ on research and development, open approaches to research and development and innovation, pooled funds, direct grants to companies, milestone prizes and end prizes and patent pools. They made recommendations on how much they thought countries should contribute to financing research and development activities, and also suggested that the WHO should take a coordinating role, including a global health research and development observatory. Another example of promoting innovation may be the increasing number of public-private partnerships. There are the well-established entities, such as MMV and DNDi who have a portfolio of products for malaria and neglected tropical disease respectively. New products from both are on the market. Another venture, the Innovative Medicines Initiative is the biggest public-private partnership to date, and is also hoping to promote the development of innovative medicines.

Patents or patients: who loses?

The unprecedented weakening of patent rights in the United States undermines necessary incentives for the discovery and development of innovative medicines.

Studies on pharmacological activity of borneol

Borneol is a major component of many medicinal plant essential oils, as well as a popular traditional Chinese medicine. This essay collects the results of the latest domestic and foreign studies, and summarizes and analyzes its activity and reaction mechanism on analgesia, putridity elimination and flesh regeneration, and repair of damaged cells. Moreover, it proposes problems concerning borneol during medical studies, providing support for the in-depth study and exploration of efficacies of precious traditional Chinese medicines as well as the effective utilization and development of innovative medicines.

Assessing Stakeholder Opinion on Relations between Cancer Patient Groups and Pharmaceutical Companies in Europe

The relationship between the pharmaceutical industry and cancer patient groups has been the subject of much scrutiny and skepticism, and some high-profile negative media coverage has focused attention on some of the problematic aspects of the relationship. Both the pharmaceutical industry and cancer patient groups have made an effort in recent years to improve the transparency and openness of their relations, specifically with regard to the financial support offered by pharmaceutical companies to patient groups. The objectives of this survey were to benchmark perceptions held by different stakeholder groups about current relationships between cancer patient groups and pharmaceutical companies in Europe, and to explore opinions about ways in which partnerships between patient groups and pharmaceutical companies could evolve to the benefit of cancer patients. The survey was conducted using a structured questionnaire that contained a combination of matrix, scaled, and open-ended questions. The questionnaire was developed based on a literature search and the findings from ten in-depth interviews conducted with policy makers and advocates working at an EU level. Telephone interviews were carried out using a structured questionnaire with a convenience sample of 161 policy makers, cancer healthcare group representatives, and cancer patient group leaders from France, Germany, Hungary, Italy, Latvia, the Netherlands, Poland, Portugal, Romania, Spain, Sweden, and the UK. The interviews took place in the relevant language of the country. The current relationship between the pharmaceutical industry and cancer patient groups in Europe is generally viewed as positive, but it is also viewed as being unequal, not transparent enough, and not sufficiently patient-centric. There is broad agreement that cancer patient groups can help companies identify unmet needs and contribute to the development of innovative medicines; however, there is some concern about cancer patients' competence to take on this role. Also, pharmaceutical companies and patient groups have a common interest in working together on the development of non-promotional patient information and strategies to support medicines adherence. Respondents also indicated that the two sectors have a legitimate interest in ensuring that patients in need access appropriate treatments in a timely manner. Ongoing cooperation between health professionals, pharmaceutical companies, and cancer patient groups is also viewed as important. Efforts should continue to make relations between pharmaceutical companies and cancer patient groups as equal, open, and transparent as possible. Despite ongoing concerns about the openness and transparency of relations between pharmaceutical companies and patient groups, there is scope for these two sectors to work together on issues of common interest.

The Contradictions of the State Policy on Regulation of Prices on Medicines: Problems and Ways of Their Solving

The article analyzes the existing model of regulation of prices on medicines in the Russian Federation. Problems of this model are described (especially the fact that it stimulates elimination of cheaper medicines from the product range of pharmacies and pharmaceutical distributors and hinders investments into local development of innovative medicines). Ways to solve these problems are proposed. It is demonstrated that all medicines should be divided into three groups according to their price, and for each group a special method of price regulation should be used. It is also proposed to implement a guaranteed level of profitability of local developers of innovative medicines.

The dilemma of intellectual property rights for pharmaceuticals: the tension between ensuring access of the poor to medicines and committing to international agreements.

In this paper, we provide an overview of how the outcomes of the Uruguay Round affected the application of pharmaceutical intellectual property rights globally. Second, we explain how specific pharmaceutical policy tools can help developing states mitigate the worst effects of the TRIPS Agreement. Third, we put forward solutions that could be implemented by the World Bank to help overcome the divide between creating private incentives for research and development of innovative medicines and ensuring access of the poor to medicine. Fourth, we evaluate these solutions on the basis of utilitarian considerations and urge that equitable pricing is morally preferable to the other solutions.

Moving Beyond Combinatorial Chemistry for Greater Efficiency in Lead Discovery

Pfizer Inc. is a research based global pharmaceutical company committed to the discovery and development of innovative medicines that improve the quality of life of individuals throughout the world...