ArchiveInnovative drug companies can obtain patent rights and exclusive rights for drug trial data for new drugs, their initial uses and new uses developed in the future. Both rights are exclusive rights, which are designed to protect innovative drug companies in their predominant position in the market. The initial exclusivity and subsequent exclusivity of innovative drugs constitute institutional barriers to the marketing of generic drugs. However, in the practice of the United States, once the initial exclusivity expires, generic drugs will be encouraged to enter the market. Actually, subsequent exclusivity cannot prevent the process of the replacement of innovative drugs by generic drugs. This article analyzes the practical measures of American society to break through institutional barriers from three aspects of administrative supervision, medical practice and judicial relief, and finds that the evasion of subsequent exclusive rights by stakeholders in administrative supervision. Furthermore, medical practice is the main reason for the breakthrough of institutional barriers. The difficulty of asserting the subsequent exclusivity is the secondary reason for the breakthrough of institutional barriers.
Capmatinib is a hepatocyte growth factor receptor (MET) inhibitor, which was approved by the US FDA on May 6, 2020 for the treatment of adult patients with non-resectable locally advanced or metastatic non-small cell lung cancer with MET14 exon jumping mutation. This approval means another significant innovation in the treatment of NSCLC patients with MET mutation after the listing of Tepmetko®. In this paper, the mechanism of action, pharmacokinetics, pharmacodynamics, clinical research, safety and intellectual property right of the drug were reviewed.
The paper analyzed the status quo of new Chinese herbal drug (NCHD) approval and registration in recent years, discussed the characteristics and existing problems of NCHD, then provided feasible suggestions. From 2012 to 2019, the number of NCHD approval showed a downward trend, but the approval rate increased. From 2015 to 2020, the number of NCHD registration decreased significantly, the number of category 6 new drugs had the largest number of registration, and there was no registration of category 2 and new drugs of category 4. The regional distribution of declaration units was obvious, the top 5 regions accounting for 48% of the total number of applications. The new drugs were mainly oral preparations, and the treatment field was concentrated in major common diseases. The sources of NCHD were mainly clinical prescriptions and scientific research achievements of scientific research institutions. In general, the quality of NCHD application has been improved, but the amount is at low tide. All stakeholders need to take multiple measures to promote the research and development of NCHD.
The reproductive and developmental toxicity evaluation on non-human primates is required urgently as the booming of biotechnological drugs. The selection of positive drugs is vital for establishment of the test system when there is less experience in domestic safety evaluation centers. There are different kinds of teratogens reported to both human and animals such as rodents, rabbits, but less on non-human primates. In this paper the potential teratogens to non-human primates were reviewed according to the literature.
Idiopathic pulmonary fibrosis (IPF) is the most common, fatal interstitial lung disease with unknown etiology. The current hypothesis is that sustained injury imposed on alveolar epithelial cells leads to aberrant wound healing and finally pulmonary function failure. The unknown pathogenesis heightens the difficulty for anti-fibrosis drug development. Only two drugs, pirfenidone and nintedanib, are approved for IPF treatment, and medical therapies against IPF are still in urgent need. Now researchers are focusing on new indications development for approved drugs since they have relatively detailed pharmacokinetics and safety data. Thus, effective drugs will rapidly go to clinical trials, and the development cycle will be greatly shortened. Here we summarize the basic science studies for different types of approved drugs against IPF and hope to provide reference for development of anti-fibrosis drugs.
The international status of traditional Chinese medicines is constantly improving, and the research of modern pharmacology on their active ingredients and pharmacological activities promotes the development and clinical application. However, with the increasing application of traditional Chinese medicines, more attention should be paid to their toxicity and clinical side effects. Most Chinese medicinal materials have cardiovascular toxicity and poor clinical prognosis, which is also the main factor of death caused by excessive use. Therefore, it is vital to explore the cardiotoxicity of traditional Chinese medicines applied in clinic, seek efficient preventive measures and look for treatment methods. In “the measures for the management of toxicity for medical use”, Datura metel L, Aconitum carmichaeli Debx, Realgar, Hyoscyamus niger L, Hydrargyri oxydum Rubrum, Aconitum vilmorinianum Kom, Strychnos nux-vomica L, Toad venom, Euphorbia Lathyris L, Aconitum brachypodun Diels, Radix Aconiti, Realgar, Calomelas, Hydrargyrum and Mylabris phalerata Pallas are defined as toxic herbs. In this paper, the existing literature is reviewed to summarize the toxic and side effects of toxic traditional Chinese medicines on cardiovascular system, as well as the detoxification methods, so as to provide references for the clinically effective treatment of toxic traditional Chinese medicines.
Sodium-dependent glucose transporters 2 inhibitors (SGLT2i), as a new hypoglycemic drugs, are associated with renal tubular reabsorption of glucose. In several large-scale clinical randomized controlled trials, SGLT2i decreased the incidence of end-stage renal disease and the demand for dialysis or transplantation due to kidney disease. Its renoprotective effect is far beyond its hypoglycemic effect. Considering that other drugs with stronger hypoglycemic effect have not gained similar benefits, SGLT2i obviously has a renal protective mechanism outside hypoglycemic effect, becoming the hot spot for clinical treatment and research field at present. In this paper, the relevant functions and mechanisms are reviewed.
Patient-reported outcome (PRO) data from clinical trials is strong evidence which can inform shared decision-making, labeling claims, clinical guidelines, and health policy; however, those data is often not given enough emphasis to in current clinical trial protocols. The “Standard Protocol Items: Recommendations for Interventional Trials” (SPIRIT) statement, using the most concise items by providing evidence-based medicine, aims to improve the completeness of trial protocols. However, it does not provide guidance on PRO content. The SPIRIT-PRO Extension provides minimum requirements for PRO which will be used as the primary or key secondary study endpoint in clinical trials. Improved design of clinical trials including PRO could help ensure high-quality data that may inform patient-centered care. We interpreted the key contents of this extension, including the normative methods for the management, collection and analysis of PRO data, in order to provide references for clinical trial researchers.
A pediatric clinical trial is a systematic study of a drug in people aged 0~18 years. Due to the specialness of the subjects, the process management of pediatric clinical trial is particularly important. Whether a high-quality pediatric clinical trial can be carried out directly affects the marketing speed of pediatric drugs, and then affects the accessibility of pediatric drugs. At present, there are still some problems in pediatric clinical trials in China, such as difficulty in recruiting subjects, lack of high-quality standard management in the trial process, and lack of rigor in the ethical review. Based on a comprehensive analysis of the policies, measures and regulatory experience in promoting the development of pediatric clinical trials in the United States, this paper compared the relevant policies and regulatory systems of pediatric clinical trials in China with those in the United States, and analyzed the problems existing in the management of pediatric clinical trials in China, so as to propose countermeasures and suggestions for improving our management of pediatric clinical trials.
To build a more stable, reliable and practical model for the probability prediction of a lead compound becoming a drug based on the deep learning method.
The positive and negative sample data sets were collected from Iintegrity, Chembl and Drugbank databases firstly. After cleaning the large data set of positive and negative samples and solving the problem of data imbalance, the compounds' SMILES were further encoded. Then, Stacked AutoEncoder (SAE) and Fully Connected Neural Network (FCNN) were used to construct and train the deep neural network model to extract the features of the compounds and predict the probability of a lead compound becoming a drug.
The model finally converged stably, the ACC value and AUC value reached 0.995 3 and 0.992 9 respectively on the validation set, which improved the prediction accuracy by about 3% compared with the previously reported model based on machine learning.
The prediction model based on large data set and deep neural network technology has certain practicability, and can improve the accuracy of the probability prediction of a lead compound becoming a drug.
To establish a method of stimulating human ovarian granulosa cells KGN to secrete progesterone (PG) by human menopausal gonadotropin (HMG), based on the mechanism of estrogen stimulating the production of progesterone in ovarian granulosa cells in mammalian, to evaluate the titer of follicle-stimulating hormone (FSH), the active component of HMG.
KGN cells were stimulated with different concentrations of HMG solution, the content of PG in the secreted supernatant was detected, and the biological activity assay of FSH in vitro was established. According to the 9101 analysis method verification and 9401 biological products bioactivity/potency determination method verification guiding principles in the General Rules of the fourth part of Chinese Pharmacopoeia, the established method was validated in terms of specificity, precision and durability. The national standard of HMG was used as the benchmark to detect the potency of HMG international standard and preparation (qualified and unqualified).
Different concentrations of HMG displayed effect on KGN cells in a time- and dose-dependent manner.
The specificity, precision and durability of the method meet the requirements of the General Principles of the fourth part of Chinese Pharmacopoeia. Based on HMG national standard, the titers of HMG international standard and HMG for injection can be effectively determined, with consistent results with the pharmacopoeia method.
To investigate the changes of the plasma metabolic spectrum of C57BL/6 young mice treated with different doses of nano-TiO2, explore the possible mechanism of its toxic side effects, and identify its toxicity-related biological targets.
Mice were randomly assigned to receive nano-TiO2 at doses of 0 (control group), 10, 30, 100, or 300 mg·kg-1. The plasma data were analyzed using UPLC-MS technology combined with principal component and partial least squares analyses. The results revealed differences between the control group and each nano-TiO2 group, with the effect becoming more pronounced with increasing doses. Topological analysis of the different metabolites was conducted using the Pathway Analysis database.
In total, 35 different metabolites were screened from plasma, and Nano-TiO2 treatment was revealed to affect linoleic acid metabolism, biosynthesis of valine, leucine and isoleucine, sphingolipid metabolism, arachidonic acid metabolism, glycerophospholipid metabolism, nicotinate and nicotinamide metabolism, histidine metabolism, and other pathways.
The results indicated that the toxicity mechanism of Nano-TiO2 after 28 days of exposure may be related to abnormal amino acid and lipid metabolism.
To analyze polymer impurities in cefathiamidine for injection by different methods, and compare the advantages and disadvantages of the specificity of different methods.
By using Sephadex G-10 System, high performance gel chromatography and column switching-LC-MSn method, the polymers in cefathiamidine for injection from 11 manufacturers were analyzed.
No polymer was detected by Sephadex G10 System, high performance gel chromatography could detect polymer impurities, the structure of the components separated by high performance gel chromatography system was confirmed by the column switching-LC-MSn method.
It was proved that there were some polymer impurities in cefathiamidine for injection, the Sephadex G10 System and high performance gel chromatography had poor specificity, and macromolecular polymers and small molecular impurities could not be separated and qualitatively analyzed. This study laid the foundation to further establish a better specificity method.
To verify the method of bacterial endotoxin test for octreotide acetate microspheres for injection.
According to the bacterial endotoxin test method of Chinese Pharmacopoeia (2020 edition), octreotide acetate microspheres for injection was dissolved by DMSO and diluted with water. Interference test and endotoxin recovery test were carried out with two manufacturers' gel limulus amebocyte lysate.
There was no interference between bacterial endotoxin and limulus reagent when the concentration of octreotide acetate microspheres for injection was diluted to 0.007 mg·mL-1. The recovery of bacterial endotoxin in DMSO solution was between 50% and 200%. DMSO can be used for dissolving octreotide acetate microsphere to perform bacterial endotoxin test.
Bacterial endotoxin test is suitable for the detection of octreotide acetate microspheres for injection.
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