A study of new drug approval pattern of a Southeast Asian developed country from 2017 to 2021

Background: The pattern of new drug approval is changing across the world as shown by the study using Center for Drug Evaluation and Research and European Medicines Agency data in US and UK with more drug approval for anti-cancer and immunomodulator drugs. There is a need to generate similar database for developed South East Asian countries too. Aims and Objectives: This study was conducted for one such country- Singapore for the new drug approval pattern of last 5 years (2017–2021). Materials and Methods: This was a pharmacoepidemiological study, in which government drug regulatory website data available in public domain was searched. The new drug approval data were classified according to active ingredient, drug approval date, new drug application category, indication of drugs, and World Health Organization Anatomic Thoracic Classification. Results: In this study, 418 new drug approvals were found in last 5 years in Singapore. From this maximum, drug approvals were given to anti-neoplastic and immunomodulator category drugs. In anti-neoplastic category new drugs approval few examples were Trastuzumab deruxtecan and Tucatinib for breast cancer therapy and Tepotinib and Capmatinib for non-small cell lung cancer therapy. Conclusion: This study shows that drug development in anti-cancer drug and immunomodulator is significant in Singapore. This trend is quite matching with other country such as US and UK.

Current status and new progress of drug therapy for premature ejaculation / 现代泌尿外科杂志

Premature ejaculation (PE) is the most common male sexual dysfunction with a high incidence, which seriously affects the relationship between a husband and wife and family harmony. Drug therapy is a first-line treatment for PE patients with premature ejaculation, and has achieved good efficacy, but the clinically available drugs are single and the abandonment rate is high. Coupled with the ineffective treatment of some patients, new drug research and development is imminent. This paper systematically reviews the current status of drug treatment for premature ejaculation, focusing on the research and development of new drugs and research progress in order to provide a reference for clinicians.

ETCM v2.0: An update with comprehensive resource and rich annotations for traditional Chinese medicine

Existing traditional Chinese medicine (TCM)-related databases are still insufficient in data standardization, integrity and precision, and need to be updated urgently. Herein, an Encyclopedia of Traditional Chinese Medicine version 2.0 (ETCM v2.0, http://www.tcmip.cn/ETCM2/front/#/) was constructed as the latest curated database hosting 48,442 TCM formulas recorded by ancient Chinese medical books, 9872 Chinese patent drugs, 2079 Chinese medicinal materials and 38,298 ingredients. To facilitate the mechanistic research and new drug discovery, we improved the target identification method based on a two-dimensional ligand similarity search module, which provides the confirmed and/or potential targets of each ingredient, as well as their binding activities. Importantly, five TCM formulas/Chinese patent drugs/herbs/ingredients with the highest Jaccard similarity scores to the submitted drugs are offered in ETCM v2.0, which may be of significance to identify prescriptions/herbs/ingredients with similar clinical efficacy, to summarize the rules of prescription use, and to find alternative drugs for endangered Chinese medicinal materials. Moreover, ETCM v2.0 provides an enhanced JavaScript-based network visualization tool for creating, modifying and exploring multi-scale biological networks. ETCM v2.0 may be a major data warehouse for the quality marker identification of TCMs, the TCM-derived drug discovery and repurposing, and the pharmacological mechanism investigation of TCMs against various human diseases.

Research advances on the role of epigenetic modifications in the long-term progression of alcoholic liver disease / 药学学报

There are more than 60 million alcoholic liver disease (ALD) patients in China, which has become a public health problem that cannot be ignored. Moreover, the social problem of "alcohol culture" is still hardly to solve, so that safe and effective prevention and treatment for ALD are in urgent need clinically. Previous studies on ALD have focused on the direct damaging effects of alcohol and its toxic metabolites, while recent studies have shown that the pathogenesis of ALD also include alcohol metabolic reprogramming and endogenous metabolites disorder. Although the endogenous metabolites have no direct toxicity, its long-term effect should not be ignored. These endogenous metabolites could change epigenetic modifications, cause widespread and persistent abnormal gene expression and signal pathway activation abnormally to promote metabolic reprogramming and stamp it as "metabolic memory", which manifest pathological changes and promote ALD, especially liver fibrosis/cirrhosis and liver cancer. Based on this, the article reviews the important epigenetic modifications caused by related metabolites in ALD and their associated effects. The role of traditional Chinese medicine (TCM) and its active ingredients in regulating epigenetics was also analyzed. The results suggest that regulation of epigenetics and alteration of "metabolic memory" may be a novel mechanism of TCM in the prevention and treatment of ALD.

Deep learning-based de novo drug design: principles, tools and practice / 药学学报

Design of structurally-novel drug molecules with deep learning can overcome the technical bottleneck of classical computer-aided drug design. It has become the frontier of new technique research on drug design, and has shown great potential in drug research and development practice. This review starts from the basic principles of deep learning-driven de novo drug design, goes on with the brief introduction to deep molecular generation techniques as well as computational tools and the analysis on representative successful cases, and eventually provides our perspective for future direction and application prospect about this technique. This review will provide ideas on new technique research and references for new drug research and development practice to which this technique is applied.

Considerations on pivotal clinical trial design of innovative new drugs for hematological malignancies / 白血病·淋巴瘤

The rapid changes in the research and development environment of new anti-tumor drugs in China have brought various challenges to drug innovation. How to explore the clinical advantages of new drugs in the early phase, and design scientific, reasonable and efficient pivotal clinical trials for drug registration accordingly, is one of the key challenges. This article takes innovative new drugs for hematological malignancies as an example, comprehensively elaborates the considerations on the timing for entering the pivotal clinical trial and the key elements of the trial design from the perspective of clinical reviewers.

A Propensity Score Matching Study of Autologous Hematopoietic Stem Cell Transplantation and New Drug Chemotherapy for Newly Diagnosed Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To compare the clinical efficacy, survival, and prognosis of autologous hematopoietic stem cell transplantation (ASCT) with new drug chemotherapy in the treatment of newly diagnosed multiple myeloma (NDMM) in the new drug era.@*METHODS@#The clinical data of 149 patients with NDMM treated with new drug induction regimen in Union Hospital, Tongji Medical College, Huazhong University of Science and Technology from January 2012 to December 2019 were retrospectively analyzed. Twenty-four patients who received ASCT were in ASCT group, and 125 patients who did not receive ASCT were in non-ASCT group. The median follow-up time was 43 (1-90) months. The propensity score matching (PSM) method was used to balance confounding factors, then depth of response, overall survival (OS), and progression-free survival (PFS) between the two groups were compared and subgroup analysis was performed.@*RESULTS@#After matching, the covariates were balanced between the two groups. Fifty-one patients (15 cases in ASCT group and 36 cases in non-ASCT group) were included. ASCT patients had a better complete response (CR) rate than non-ASCT patients receiving maintenance therapy (93.3% vs 42.3%, P=0.004), while there were no statistical differences in deep response rate and overall response rate (ORR) between the two groups (93.3% vs 65.4%, P=0.103; 93.3% vs 96.2%, P=1.000). Before matching, the 3 and 5-year PFS rate and median PFS (mPFS) in ASCT group and non-ASCT group were [89.6% vs 66.5%, P=0.024; 69.8% vs 42.7%; non-response (NR) vs 51.0 months], and the 3 and 5-year OS rate and median OS (mOS) were (100% vs 70.6%, P=0.002; 92.3% vs 49.6%; NR vs 54.0 months). After matching, the 3 and 5-year PFS rate and mPFS in ASCT group and non-ASCT group were (83.6% vs 61.7%, P=0.182; 62.7% vs 45.7%; NR vs 51.0 months), the 3 and 5-year OS rate and mOS were (100% vs 65.6%, P=0.018; 88.9% vs 46.9%; NR vs 51.0 months). Subgroup analysis showed that patients with mSMART 3.0 high risk stratification, the 3-year PFS rate and mPFS in ASCT group and non-ASCT group were (83.3% vs 41.5%, P=0.091; NR vs 34.0 months), and the 3-year OS rate and mOS were (100% vs 41.5%, P=0.034; NR vs 34.0 months). Patients with mSMART 3.0 standard risk stratification, the 3-year PFS rate and OS rate in ASCT group and non-ASCT group were (83.3% vs 76.8%, P=0.672; 100% vs 87.2%, P=0.155). The 3-year PFS and OS rate in MM patients who achieved deep response within 3 months after transplantation compared with non-ASCT patients who achieved deep response after receiving maintenance therapy were (83.1% vs 56.7%, P=0.323; 100% vs 60.5%, P=0.042), and the 3-year PFS and OS rate in patients who achieved overall response in both groups were (83.1% vs 62.5%, P=0.433; 100% vs 68.1%, P=0.082). After matching, Cox multivariate regression analysis showed that mSMART 3.0 risk stratification and ASCT were independent prognostic factors for OS.@*CONCLUSION@#In the new drug era, ASCT can increase CR rate and prolong OS of NDMM patients. ASCT patients who are mSMART 3.0 high risk stratification or achieved deep response within 3 months after transplantation have better OS than non-ASCT patients receiving new drug chemotherapy. ASCT and mSMART 3.0 risk stratification are independent prognostic factors for OS in NDMM patients.

Rethinking the marketing strategy of anti-tumor drugs by single-arm trials supported / 中华肿瘤杂志

Single-arm trial refers to a clinical trial design that does not set up parallel control group, adopts open design, and does not involve randomization and blind method. These features, on the one hand, speed up the process of clinical trials, significantly shorten the time to market and meet the needs of patients with advanced malignancies, but also lead to the uncertainty of single-arm clinical trials themselves. Recently, the US Food and Drug Administration held a meeting of the oncologic drug advisory committee to discuss six tumor indications that have been accelerated approved, which once again triggered the discussion of single-arm trials. The basis of accelerated approval by single-arm trial is actually a compromise on the level of evidence-based medical evidence requirements after assessing the benefit risk. Therefore, the sponsor should strictly grasp the applicable conditions of single-arm trial in anti-tumor drugs and conduct single-arm trial scientifically. Post-marketing clinical trial should be implement as early as possible to ensure the benefit of patients. Based on the characteristics of single-arm trial, combined with two guidance relevant to single-arm trial issued by National Medical Products Administration recently, this article is supposed to propose and summarize the strategy of single-arm trial supporting the marketing of anti-tumor drugs.

Chemical Compositions and Anti-tumor Effect of Tetrastigma hemsleyanum： A Review / 中国实验方剂学杂志

Due to the infinite proliferation， strong migration and loss of contact inhibition of tumor cells， tumor has become the most intractable diseases to be cured in the world. At present， the main treatments of tumor diseases are surgical resection， radiotherapy， chemotherapy， targeted-therapy and immunotherapy. Although these measures can inhibit or kill the tumor to a certain extent， they still cannot avoid adverse reactions and drug resistance. After thousands of years of clinical practice， traditional Chinese medicine （TCM） has the characteristics of good curative effect， few adverse reactions and significantly improving the quality of life in patients， which provides new ideas for the prevention and treatment of tumors. As an endemic and rare plant in China， Tetrastigma hemsleyanum has been listed in the 2015 edition of Zhejiang Provincial Processing Specification of TCM with the effects of heat-clearing and detoxification， detumescence and analgesia， dissipating phlegm and resolving masses. It has been reported that the chemical constituents of T. hemsleyanum are mainly flavonoids， polysaccharides， phenolic acids， terpenoids， steroids， volatile oils， alkaloids and so on. It can exert a broad spectrum of anti-tumor effects through various ways such as inhibiting proliferation， migration and invasion of tumor cells， inducing apoptosis of tumor cells， inhibiting angiogenesis of tumor cells， reversing multidrug resistance of tumor cells and regulating body autoimmunity. On the basis of reviewing relevant literature at home and abroad， this paper intends to systematically sort out the chemical and anti-tumor research of T. hemsleyanum， and in order to provide a new idea for its synergistic anti-tumor effect of multi-component， multi-pathway and multi-target， and finally provide theoretical basis for the research and development and clinical application of new anti-tumor drugs of T. hemsleyanum.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics (DMPK) is an important branch of pharmaceutical sciences. The nature of ADME (absorption, distribution, metabolism, excretion) and PK (pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems. Tremendous progress has been made in the past decade, not only in the characterization of physiochemical properties of drugs that influence their ADME, target organ exposure, and toxicity, but also in the identification of design principles that can minimize drug-drug interaction (DDI) potentials and reduce the attritions. The importance of membrane transporters in drug disposition, efficacy, and safety, as well as the interplay with metabolic processes, has been increasingly recognized. Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs, such as peptides, oligonucleotides, and antibody-drug conjugates, necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties. In this review, we highlight some of the most notable advances in the last decade, and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Challenges of Investigator-initiated Clinical Trials to Support the New Drug Development / 中国肺癌杂志

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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Discussion on the Focus of On-site Inspection of Clinical Trials of Lung Cancer Targeted Therapy and Immunotherapy Drugs / 中国肺癌杂志

As lung cancer targeted therapy and immunotherapy drugs are the current hot spot in the research and development area of new anti-tumor drugs, the amount of clinical trial in this area is increasing year by year. On the basis of combing the on-site inspections of drug registration clinical trials from 2019 to 2021, combined with the characteristics of lung cancer targeted therapy and immunotherapy drugs, this paper discusses the focus of on-site inspection of clinical trials of such drugs, and puts forward suggestions for the compliant implementation of lung cancer clinical trials.
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Application of pharmacomicrobiomics in new drug development / 中国临床药理学与治疗学

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.

Application and prospect of organoid culture in cancer / 中国药理学通报

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.

Guidelines investigation and technical considerations of virus safety during investigational new drug application of innovative monoclonal antibody products / 药学学报

With the development of antibody manufacturing technology and improvement of new drug research in domestic industry, more innovative monoclonal antibody products submitted investigational new drug (IND) application. At the same time, monoclonal antibody products from abroad which have been approved marketing authorization and/or conducted clinical trials submitted IND applications in China. The National Medical Products Administration (NMPA) issued the "Guideline of Investigational New Drug Application" (No. 16, 2018) which emphasized the chemical, manufacturing, and control (CMC) regulatory, and dossier requirements in IND application, greatly promoted the application quality of innovative biological products. However, compared to the Food and Drug Administration (FDA) and European Medicines Agency (EMA), our particular guidelines are insufficient, such as guideline on virus safety evaluation of biotechnological investigational medicinal products. This review investigated the questions raised by sponsors from 2018 to 2020, including the end of production cell (EOPC) and/or unprocessed bulk (UPB) testing and virus removal or inactivation validation. Meanwhile, sponsors submitted different dossiers due to differences in understanding of stage requirements of guidelines from domestic and abroad. Based on the guidelines of virus safety from NMPA, FDA, and EMA, and the technical considerations, this review puts forward personal suggestions on the adventitious agents testing and virus removal or inactivation validation in manufacturing process, aim to ensure virus safety of innovative monoclonal antibody products in clinical trials.

Applications of model-informed drug development (MIDD) on new drug research and development / 中国临床药理学与治疗学

Model-informed drug development (MIDD) refers to the application of various mathematical models in drug development, in order to facilitate the decision-making process. There have been common and mature applications of MIDD to address drug development and regulatory questions in interactional industries and advanced regulatory agencies, especially the US FDA. However, its application in innovative drug development is relatively rare in China. Representative case studies, clinical pharmacology review ex-periences, and relevant guidelines are reviewed in this article to present a preliminary discussion on the main applications of MIDD. Additionally, several suggestions for the application of MIDD in new drug development as well as general considerations for new drug registration are proposed in this paper, for the discussion or reference of industries and researchers.

Discussion on the format and content of new drug population pharmacokinetic study report / 中国临床药理学与治疗学

Population pharmacokinetics (PopPK) is an analytical method that can quantify the variability of drug concentration among individuals. It is widely used in various stages of new drug researches from non-clinic to clinic. With the rapid development of PopPK, more and more sponsors are keen to comprehensively analyze the in vivo processes of new drugs as well as its influencing factors using modeling and simulation methods. Several guidelines have been issued to recommend the use of PopPK in China. However, no explicit requirement of PopPK study report has been issued for regulatory application. This article conducts a preliminary discussion on new drug PopPK study and its reporting format and content, with reference to the requirements in relevant guidelines as well as previous review experiences, for the discussion or reference of industries and researchers.

Therapeutic drugs and treatment of SARS-CoV-2 / 中国临床药理学与治疗学

Novel coronavirus pneumonia caused by the SARS-CoV-2 appeared in Wuhan, China in December 2019. The virus spread rapidly across the country and resulted in the infection of more than 80 000 people by March 8, 2020. This paper introduces the data of tested drugs in vitro, in animal and in clinical trials marketed and in research, in hoping of providing reference for the prevention and control of SARS-CoV-2.

Chinese medicine theory research on syndrome new drug development--research on intervention modes of Chinese medicine based on ancient literature / 中国中药杂志

Disputes about the research and development of syndrome traditional Chinese medicine(TCM) new drug in Guidance for syndrome TCM new drug development still exist, including the fact that it is unclear whether the compound TCM preparations just targeting a sort of syndrome is in line with the TCM theory and that it is obscure what are clinical advantages of syndrome new drug as compared with new drug targeting both disease and syndrome. Based on TCM classical theory, dating back to intervention opinions of successive dynasties, theory of three-dimensional N levels was proposed from the aspects of intervention modes, intervention latitudes and formulae to illustrate that the syndrome TCM new drug is in line with TCM theory. As for the first dimension, the intervention modes of TCM could be classified into targeting disease, targeting pathology and targeting symptoms, and the basic elements were extracted as constitution, disease, pathogenesis, pathology, location, symptoms, Western medicine pathology and Western medicine indicators. Among them, the mode targeting TCM constitution and the mode targeting pathology provided the theoretical possibility of TCM syndrome new drug, while the mode targeting disease was suitable for disease syndrome new drug. As for the second dimension, the intervention latitudes were summarized, including Yin-Yang, Qi-blood-body fluid, viscera, meridian, tri-jiao, Wei-Qi-Ying-blood, six channels, and local part. The relatively broad latitudes such as Yin-Yang, Qi-blood-body fluid, and meridian might be suitable for the development of TCM syndrome new drug. As for the third dimension, the TCM formulae could be divided into four types according to the range of indications, including broad indications, viscera pathogenesis indications, disease-targeting indications and symptom-targeting indications. The first two types were suitable for TCM syndrome new drug development, while the disease-targeting indication type fit for disease-syndrome new drug. According to theory of three dimensional N levels, the clinical orientation of syndrome TCM new drugs and their advantages over disease-syndrome new drugs were as follows: syndrome TCM new drugs may be considered for novel disease without clear basic pathogenesis or advance regulation, complicated diseases, complicating diseases, geriatric disease and ba-lancing TCM constitution.

Analysis of Excretion Behavior of GK-A from Ginkgo Semen in Urine and Bile of Rats / 中国实验方剂学杂志

Objective::To investigate excretion of GK-A, a antitussive compound separated from Ginkgo Semen, in the urine and bile of rats. Method::UPLC-MS/MS was used to determine the concentration of GK-A in rat urine and bile samples. The separation was performed on a C18 column, the mobile phase consisted of 0.1%formic acid aqueous solution (A) and acetonitrile (B) for gradient elution (0-1 min, 95%A; 1-3 min, 95%-85%A; 3-7.5 min, 85%-40%A; 7.5-8 min, 40%A). The detection was carried out by a triple quadrupole mass spectrometer in the positive ion mode with an electrospray ionization (ESI). Multiple reaction monitoring (MRM) mode was employed. After intragastric administration of GK-A, the urine and bile samples were collected at different time points, and the contents of GK-A in the samples were determined, and the cumulative excretion and cumulative excretion rate were calculated. Result::After 72 h of administration, the cumulative excretion of GK-A in urine was (12.35±2.69) μg, and the cumulative excretion rate was (0.58±0.13)%. Meanwhile, after 24 h of administration, the cumulative excretion of GK-A in bile was (55.16±29.22) μg, and the cumulative excretion rate was (1.57±0.83)%. Only a small amount of GK-A was excreted from urine and bile of rats with a slow speed. Conclusion::After intragastric administration, the excretion of GK-A in rat urine and bile is not the main elimination pathway.