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A large number of investigator-initiated clinical trials (IIT) were conducted in China, some of them should play an important supporting role in new drug development. Due to the large number, small scale and uneven quality of IIT in China, especially a big gap between the IIT and industry-sponsored trials in terms of protocol design, quality management and ethical review, many IIT can't be used to support the new drug development. Therefore, it is necessary for regulatory authorities, sponsors, research institutions, ethics committees and researchers to improve their understanding of the role of IIT. In order to support the new drug development with high-quality IIT, formulating supervising system, establishing an effective quality management system, enhancing the training of researchers and improving the ability of ethical review should be implemented effectively. .
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Humans , China , Drug Development , Lung Neoplasms , Research PersonnelABSTRACT
Pharmacogenomics promotes the success rate and efficiency of new drug development by targeting host genes. However, host gene level cannot fully explain the difference of drug efficacy among individuals. Pharmacomicrobiomics is an important extension of pharmacogenomics, which studies the effects of gut microbiome on drug safety and efficacy. At present, big data, Multinomial analysis, fecal bacteria transplantation, synthetic biology and other disciplines and technologies related to gut microbiome have been gradually applied in new drug development. This review introduces the current situation of new drug development and the interaction between gut microbiome and drugs, and summarizes the current research and development progress of gut microbiome related drugs.
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At present, the traditional models for cancer research include the 2D cell model, human tumor xenograft model and animal model. With the deepening of research, the traditional tumor model is unable to meet the needs of researchers. Organoid model is derived from the surgical specimens of tumor patients, which can completely preserve the histological and genomic characteristics of tumor. It can be used in the research of tumor pathogenesis, drug screening, personalized treatment of patients, etc. Compared with traditional model, it has the advantages of short modeling time, economic benefits and closer-ness to the characteristics of the original tumor. This paper mainly focuses on the research status of organoid technology in tumor, the application of organoid model in treatment, and the advantages of organoid model compared with traditional model, so as to provide reference for the follow-up research.
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@#The core protein allosteric modulator targets the core protein and inhibits hepatitis B virus(HBV)replication by regulating the formation of covalently closed circular DNA(cccDNA), which is expected to completely cure hepatitis B and overcome the drug resistance of nucleoside drugs. This paper reviews the replication process of HBV, the function of core proteins, the mechanism, classification and research progress of core protein allosteric modulators, lists 12 drugs, and summarizes their mechanisms, categories, chemical structures, safety, anti-HBV effects, combined drug use, etc. In addition, the advantages and problems of core protein allosteric modulators are discussed to provide references for the development of new anti-HBV drugs.
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In this report, we present a case study of how pharmacogenomics and pharmacometabolomics can be useful to characterize safety and pharmacokinetic profiles in early phase new drug development clinical trials. During conducting a first-in-human trial for a new molecular entity, we were able to determine the mechanism of dichotomized variability in plasma drug concentrations, which appeared closely related to adverse drug reactions (ADRs) through integrated omics analysis. The pharmacogenomics screening was performed from whole blood samples using the Affymetrix DMET (Drug-Metabolizing Enzymes and Transporters) Plus microarray, and confirmation of genetic variants was performed using real-time polymerase chain reaction. Metabolomics profiling was performed from plasma samples using liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. A GSTM1 null polymorphism was identified in pharmacogenomics test and the drug concentrations was higher in GSTM1 null subjects than GSTM1 functional subjects. The apparent drug clearance was 13-fold lower in GSTM1 null subjects than GSTM1 functional subjects (p < 0.001). By metabolomics analysis, we identified that the study drug was metabolized by cysteinylglycine conjugation in GSTM functional subjects but those not in GSTM1 null subjects. The incidence rate and the severity of ADRs were higher in the GSTM1 null subjects than the GSTM1 functional subjects. Through the integrated omics analysis, we could understand the mechanism of inter-individual variability in drug exposure and in adverse response. In conclusion, integrated multi-omics analysis can be useful for elucidating the various characteristics of new drug candidates in early phase clinical trials.
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Chromatography, Liquid , Drug-Related Side Effects and Adverse Reactions , Incidence , Mass Screening , Mass Spectrometry , Metabolomics , Pharmacogenetics , Plasma , Real-Time Polymerase Chain ReactionABSTRACT
Arterial thrombosis (AT) is a common disease which usually causes acute myocardial infarction,ischemic stroke and other ischemic cardiovascular and cerebrovascular diseases,which shows high rates of morbidity and mortality,and has become a serious problem to human health.It is increasingly clear that the interactions among platelets,the endothelium and leukocytes are important throughout all stages of the atherothrombotic process.It is of great significance to search for therapeutic targets in the process of AT and developing the therapeutic drugs based on those newly discovered targets.This article reviews the research advances in the discovery of antithrombotic targets and the current situation of drug development based on those antithrombotic targets found in the recent 5 years,in order to provide some references or clues for the development of innovative drugs to prevent and treat AT.
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Depression becomes more and more serious and has been greatly do harm to human's physical and mental health. WHO predicts that depression will become the second leading cause of abnormal death and disability by 2020. There is still the drug treatment as the first-line antidepressive therapy, but the effect of listed antidepressant drugs is not ideal. Therefore, discovery of new antidepressant drug of sunique, higher curative effect, less adverse reaction is the pursuit of pharmaceutical. The traditional Chinese medicine (TCM) of anti-depression and natural antidepressant in currently listed, drug development and drug discovery phase are summarized in this paper, aiming to provide reference for new antidepressant drug research.
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The flavin-containing monooxygenase (FMOs) is recognized as an important complimentary enzyme system next to the cytochrome P450 (CYP450), which catalyzes the metabolism of many xenobiotics (nucleophilic heteroatom-containing chemicals) and several endobiotics. This article provides a comprehensive introduction of FMOs including the biological characteristics, catalytic mechanism, substrate specificity, genetic polymorphisms. The effect of FMOs on drug metabolism and individual differences and relation with diseases are also mentioned. It is valuable for the discovery of therapeutic targets and design of new drug candidate.
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Neurotoxicity is one common adverse effect caused by many drugs or compounds.In the early phase of new drug development,it is necessary to screen for neurotoxicants.Neurotoxicity studies in nonhuman primates (NHP) are used to evaluate the neurotoxicity of small-molecule drugs or vaccines that may affect the nervous system across the blood-brain barrier during preclinical safety assessment.Toxicologic pathological evaluation or neuropathological examination is the "gold standard" for the evaluation of drug neurotoxicity in preclinical drug safety studies.In this paper,the majory factors influencing the quality of neuropathology evaluation in toxicology,including the general strategy of neuropathology evaluation,the optimal timing of evaluation,the specific blood-brain barrier in the nervous system,the method of sampling in the histopathology of nerve tissue,and the interference of artificial artifacts in diagnosis of neuropathology,were detailly analyzed in order to provide a reference for setting guidelines of neurotoxicity risk assessment in China and pathologists and toxicologists engaged in nonclinical neurotoxicity studies.
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Human respiratory syncytial virus (hRSV) was considered to be the leading cause of lower respiratory tract disease in infants and young children. So far, there was a lack of effective anti-hRSV drugs and vaccines. In this paper, the latest research progress on anti hRSV infection drugs was reviewed from three aspects of effective constituents of Chinese materia medica, Chinese materia medica, and Chinese medicine compound antiviral inhibitor research and development, which would lay a theoretical foundation for the research and development of anti-hRSV drugs and the anti hRSV infection treatment strategy.
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Bioequivalence has an important role in the new drug research, development of non-patent medicine, and post-marketing evaluation of drugs and is an essential step in the standardization and modernization of Chinese materia medica (CMM). With the acceleration of modernization of CMM, CMM preparation products made by different manufacturers differ in quality, resulting in different effects. Therefore, it is very important to strengthen the application of bioequivalent study in CMM preparation products to ensure the effectiveness and safety. In this paper, the research methods of the biological equivalence were introduced systematically, and the significance of the "component structure theory" to the study on biological equivalent of the CMM preparations has been elaborated, in order to improve the evaluation system of the biological equivalent for CMM preparations.
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Objective Establish an objective and fair evaluation index system for the implementation effectiveness of the National Major New Drug Development Program of China.Methods Based on literature review and Delphi method,the framework of the evaluation index system was built and analytic hierarchy process was applied to determine the priority of each indicator of the system.The objectiveness and validness of the results were assured by determining expert activeness coefficient,authority coefficient,indicator rationality,and by applying consistency check.Results A targeted and systematic evaluation index system was constructed for the National Major New Drug Development Program,and through expert consultation and analytic hierarchy process,the factor of product result was considered of the highest weight of 39.03％,followed by technical result,theoretical result and organization and management result.The evaluation index system suggested that product result and technical result are two relatively more significant factors to be considered during evaluation.Conclu sion After consultation on expert opinions,the evaluation index system for the National Major New Drug Development Program was constructed with each factor been assigned with a scientific and rational weight,and this will provide a guideline for the decision making of program administrators and evaluation practice.
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Background: The antineoplastic drugs are prescribed for the treatment of cancer, which is an important cause of mortality in India; therefore, a drug lag in the availability of antineoplastic drugs is a direct threat to life. The present study was undertaken to assess the drug lag for new antineoplastic agents in India compared with that in the United States (US) or European Union (EU). Methods: The new antineoplastic agents approved in the United States, European Union and India between 1999 and 2011 were identified and information was gathered primarily from the websites of regulatory agencies of the three regions. We assessed absolute and relative drug lag for new antineoplastic agents approved in the three regions. Results: Of the 70 new antineoplastic agents, 64 (91.42%) were approved in the United States, 54 (77.14%) in the European Union and 44 (62.85%) in India. The US was the first to approve 59 (84.28%) out of the 70 new antineoplastic agents, the EU was the first to approve 9 (12.85%) and India was the first to approve 2 (2.85%). The median approval lag for India (26.35 months) was higher as compared to the United States (0 month) and European Union (7.3 months). Conclusions: This study confirms that India’s drug lag in the case of new antineoplastic agents is higher as compared to the US and EU. Further detailed analyses are necessary to find the reasons and impacts of drug lag for antineoplastic agents in India.
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Nonclinical safety evaluation plays a critical role in the process of new drug development.International Conference on Harmonization (ICH) guideline M3 (R2) provides a key direction for the nonclinical safety evaluation process.Proper strategies and toxicological studies should be considered together to move the drug candidates forward efficiently and quickly to support clinical plans and market registration.Updates on ICH guidelines,such as ICH S6 and ICH S9,have great impact on the direction of development.With the increasing cost of development and competition in the industry,elements like predictivity,animal models,and regulatory compliance are also very important in the process.Therefore,an insight into all these factors is essential to toxicologists in the safety evaluation process.The ability to use the overall knowledge will result in a quicker and better new drug development program.
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Drug development is a lengthy, expensive, and complex process, and clinical development is the longest and the most expensive stage of drug development. To obtain market authorization of a new drug, applicants must prove the effectiveness and the safety of a drug through clinical trials. Korea has the same requirements for new drug approval as in developed countries and bridging data are required for approval of a new drug that was developed in another country. Clinical evaluation in humans consists of 3 phases, from phase 1 to phase 3, and the failure rates remain high while the clinical trial cost increases rapidly. Not only pharmaceutical sponsors but also patients and physicians want new, innovative medicines faster, simultaneously with improved productivity of drug development. With strong competition and market forces, the pressure to accelerate drug development and to predict the efficacy and safety profile of a drug candidate at an earlier stage is increasing. To improve the productivity of new drug development, modern principles of pharmaceutical sciences, clinical pharmacology, and information technology are being researched and employed by both health authorities and sponsors. Many global pharmaceutical companies are also pursuing geographical expansion strategies to enroll subjects faster among more diverse ethnic groups. To deliver innovative medicines to patients in a faster and more cost-effective ways, close and continuous collaboration among sponsors, academia, and health authorities is essential.
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Humans , Cooperative Behavior , Developed Countries , Drug Approval , Efficiency , Ethnicity , Korea , Pharmacology, ClinicalABSTRACT
Antibiotic-resistance has become a serious problem to human health. Innovative approaches are urgently required for both antimicrobial drug discovery and reversal of resistance. Great success has been achieved since the introduction of antisense technology. This review focuses on the applications of antisense technology in the aspects including identification and validation of novel antibacterial drug targets, screening of antibacterial drugs from natural products using hypersensitized strains engineered by inducible antisense RNA, and inhibition of antibiotic-resistance genes to reverse susceptibility of antibiotic-resistant strains to currently used antibiotics. In addition, the antibacterial activities, the shortcomings and prospects as antibacterial drugs of synthetic antisense oligodeoxynucleotides and their analogs are also assessed in this review.
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"Same treatment to different diseases" is the key theoretic basis for clinical research of combination of TCM and WM.The article explores its application in developing new Chinese drugs,exemplified with "Huaxia Small Onion Preparation" made by Pro.Zhang Jiemei.
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This article reviewed the appli ca tion of molecular biology technology, such as genomics, DNA labeling technology, and DNA microarray. The aim is to provide the reference for the modernization o f Chinese material medica.