ArchiveIn recent years, with the development of radiochemistry, nuclear medicine and molecular biology technology and the interdisciplinary integration, diagnostic radiopharmaceuticals have become a hot field of drug research and development at home and abroad. In the past two decades, the US FDA has approved a number of new diagnostic radiopharmaceuticals for the diagnosis of tumor, cardiovascular disease, Parkinson's syndrome and other diseases. The nonclinical study of drugs is a key part of drug development. This paper sorted out the nonclinical study information of FDA-approved diagnostic radiopharmaceuticals and summarized the focus of nonclinical study and evaluation, aiming to provide information for such drugs' development in China.
Renal cell carcinoma is a common type of urinary solid tumor. Targeted drugs have greatly improved the survival of patients with advanced renal cell carcinoma, but most patients will eventually develop drug resistance. Therefore, it is necessary to explore new treatment methods. In recent years, the application of immune checkpoint inhibitors has brought new hope to patients and further extended the survival time of patients. This article describes the key points of clinical trials for advanced renal cell carcinoma in China from the perspective of drug evaluation, aiming to provide a reference for the development of therapeutic drugs for renal cell carcinoma in China.
Because of the particularity of the production cell substrates, the potential risk of virus contamination in recombinant biological products produced by eukaryotic expression system could be introduced in various ways. Major regulatory agencies in the world-wide have issued guidelines about the viral safety in the production of such products, among which Q5A (R1), issued by the International Council for Harmonization (ICH), is widely accepted and highly recognized by different countries. In order to explore the scientific nature of the technical requirements and arouse the common thinking of the industry and regulatory authorities, this article discussed the current research progress in virus removal and inactivation process in the production of recombinant biological products from five aspects, which are the applicable scope of the guideline, new virus assays and analytical methods, the progress of validation approaches, new validation method that have emerged or evolved, and virus clearance validation and risk mitigation strategies for advanced manufacturing.
Package integrity, which is synonymous with container-closure integrity, is the ability of a package to maintain product quality, including preventing microorganism ingress and ensuring that the product meets all necessary safety and quality requirement. Package integrity assessment begins at the product development phase and continues throughout the product life cycle, which is a key consideration in the manufacturing, quality research and evaluation of sterile products. This article mainly refers to the US Pharmacopeia (USP) 〈1207〉 guidelines, based on the understanding of CMC review experience, introduces and discusses the content of container-closure integrity, including concepts and scope, the requirements of different product life cycles, testing methods and validation, etc. It is hoped that the content of this article will provide some references for the quality study and evaluation of sterile pharmaceutical products.
This paper takes the guidelines on bioequivalence study in China as the main basis, refers to the relevant requirements of international regulatory agencies, and takes the cytotoxic and small molecule targeted oral antitumor drugs as examples to give some considerations for the study design of bioequivalence of oral antitumor generics from the perspectives of science, ethics and review.
Transthyretin amyloidosis (ATTR) disease is caused by abnormal folding of transthyretin (TTR) in tissues, which mainly involves the peripheral nervous system and heart, progressively aggravates to even be life-threatening. Currently, 3 TTR-targeted therapeutic drugs have been marketed in the United States and Europe. The information from these drugs' nonclinical pharmacology and toxicology studies has important implications for 3 clinical effectiveness and safety. This article summarized the key points of the nonclinical studies of these three TTR-targeted therapeutic drugs and elaborated the focus of nonclinical study and evaluation of TTR-targeted therapeutic drugs for ATTR disease from the aspects of nonclinical effectiveness and nonclinical safety to provide information for new drug development in China.
Clinical position and effect evaluation are the key points of new drug research and development. Traditional Chinese medicine (TCM) clinical research often have problems such as unclear clinical position, effect evaluation not targeted, or do not tally with the characteristics of drug and so on. Recently, extensive investigation has been carried out with questionnaire on the revision of “the general principle of clinical research of new drug of TCM” on “how to determine the clinical position with characteristics of TCM” and “how to build effect evaluation system and evaluation standard with characteristics of TCM”, and participate experts give constructive advices. This article summarizes and analyzes experts' opinions, and discusses the author's opinion of TCM clinical position and effect evaluation system.
This article explained the purpose of analytical method validation, pointed out that there are many problems and misunderstandings about method validation in drug research and development, and gave some opinions and suggestions according to the authors' experience, expecting for higher demand from the regulatory authorities.
The COVID-19 epidemic has swept the world in 2020, posing a major threat to human life and health. The global biopharmaceutical landscape will also change. The Center for Drug Evaluation and Research (CDER) of the US FDA approved 53 innovative drugs in 2020, 40 of which were first approved worldwide. The European EMA approved 34 innovative medicines throughout the year, including 6 for the first approval in the world. Japan's Medical Products and Medical Devices Agency (PMDA) approved 38 innovative drugs throughout the year, including 13 for the first approval in the world. National Medical Products Administration (NMPA) approved 48 innovative drugs throughout the year, 9 of which were developed by local companies and approved for the first time in the world. The launch of these new drugs will provide brand new therapies or more treatment options for a variety of diseases. This paper reviewed the new drugs approved for the market in the US, EU, Japan and China in 2020, and gave a brief outlook on the new drug development in 2021, aiming to provide reference for people engaged in new drug research and development.
A total of 18 973 patents in the field of traditional Chinese medicine (TCM) from 2001 to 2019 applied by universities of China were retrieved through the incoPat patents analysis database. By statistical analysis of the application trend, the field of patents technologies, the legal status, patents transfer and licensing, foreign patents application and so on, combined with the patents analysis of typical universities in the field of TCM, this paper combed the current situation of technological innovation of TCM and patent protection in China's universities, and put forward suggestions for strengthening patent work in universities to promote technological innovation in the field of TCM.
To obtain monoclonal antibodies of the factor H binding protein (fHBP) A and B subfamily proteins in meningococcal group B, and establish an ELISA detection method which can provide a new way for quantitation and identification of fHBP antigen.
Mice were immunized with purified histidine-labeled recombinant fHBP (His), the spleen cells of mouse were fused with SP2/0 cells. 3 cell strains with stable secretion of anti-fHBP monoclonal antibodies were acquired, respectively named A, B and AB. To establish a double-antibody sandwich ELISA method for detecting recombinant fHBP antigen, AB was coated as primary antibodies, A and B were labeled by horseradish peroxidase (HRP) as the second antibody.
The GMTs valences of A, B and AB antibodies produced in mouse ascites were all between 4.4~8.8×105, and Western Blot showed that the 3 antibodies could specifically bind the corresponding recombinant fHBP antigens. The direct ELISA test also demonstrated that the 3 monoclonal antibodies merely reacted with proteins containing fHBP A or fHBP B through different recognition sites on antigens, independent of each other. The double-antibody sandwich ELISA method had good specificity and applicability, with sensitivity up to 10 ng·mL-1 and coefficient variation of less than 10%.
The double antibody sandwich ELISA method based on monoclonal antibody has good specificity and applicability, which laid a foundation to further establish a sensitive and rapid method for detection and identification of fHBP antigen.
Hyperuricemia results from excessive production of uric acid and/or physical excretion deficiency and is the core to formation and development of gout, which has caught attention of researchers due to increasing prevalence. The drugs currently used in clinic can control the development of gout, but still have various deficiencies. The hot spot of drugs under research is urate anion exchanger 1 (URAT1) inhibitor, but new conditions for old drug aiming at other targets are also worthy of attention. This article reviewed the progress in research on therapeutic drugs of hyperuricemia, aiming to provide reference for the development of new drugs.
Continuous manufacturing (CM) of solid dosage forms enables materials passing through integrated dispensing system, saving operation time and reducing human errors, thus is developing into a preferred platform for pharmaceutical products. European and American drug regulatory agencies have approved several commercial CM solid dosage form drugs. The role of control strategy for CM is based on scientific framework to identify and to reduce the risk of manufacturing variation. Process analysis technology (PAT) monitoring methods can improve product quality in real time, promote continuous improvement and innovation in manufacturing, and thus achieve advanced process control and real-time release of products. The ultimate goal is to bring safer medicines to the market more quickly and cost-effectively, as well as to achieve the digitalization and process analytics of pharmaceutical 4.0. This review article discussed the modeling and associated risk mitigation, advanced control strategies of PAT in the implementation of CM processes for solid dosage form products, and the potential challenges of regulator's expectations from industrial perspective. The current situation of new drug approvals and related PAT implementations from international pharmaceutical companies were also illustrated and discussed.
To analyze the requirements of different sponsors for serious adverse event (SAE) reporting in clinical trials and the existing problems of suspected unexpected serious adverse reaction (SUSAR) report submission after the implementation of new edition of GCP thus to give possible suggestions to guide the trial parties in drug trial safety alert work and clinical trial risk control and improve the management of SAE/SUSAR.
SAE reports of 60 applicants and SUSAR reports of 64 applicants from July 1, 2020 to December 31, 2020 were collected. Taking the report submitted by the same sponsor in the same format as one valid study sample, 62 valid original SAE reports and 87 SUSAR reports were included for the analysis.
In the submitted SAE forms, 61.3% used the template designed by the sponsors, 32.3% used the original CFDA SAE report template, 6.4% used SAE reports derived directly from EDC. Differences existed in SAE forms provided by different sponsors. For the design of these SAE forms, there were problems such as field duplicate, unreasonable setting of field options, logistic problems, missing necessary fields, handwritten filling out, unclear fonts, and so on. Among the SUSAR reports received by the institute, 38 applicants reported individual SUSAR cases, 5 out of which (13.116%) used self-made form templates, 10 out of which used the original CFDA form template (26.31%), and 23 sponsors using the CIOMS form template (60.53%), showing that CIOMS template was the most commonly used for case reports. The 49 sponsors who submitted the column matrix used different formats, fields, and varied in time of submission.
There is no unified template for the SAE report form in the industry. Sponsors need to strengthen the normative design and filling guidelines for the SAE report form, so that the researchers can fill out the SAE report more efficiently and ensure the data quality of individual case safety reports. There are significant differences in the SUSAR reports submitted to institutions and ethics committees among different applicants. Some forms are not sufficient to meet the requirements of security information review, and the time limit and frequency of submitting SUSAR reports are different. Under the above-mentioned situation institutions and ethics committees may not be able to accurately determine the risk levels of the clinical trials and subjects. So the SAE/SUSAR report forms need to be further unified and standardized.
To optimize the preparation process of Qiwei Chanshen Capsules (QCC) and conduct quality standard research.
Using the comprehensive scores of molding rate, drying weight loss, moisture absorption rate, solid density and angle of repose as characteristic index, the preparation technology of QCC was optimized using Box-Behnken design-response surface method combined with G1-entropy weight method with regard to the factors such as drug dosage, wetting agent (ethanol) concentration and drying time. Moisture, volume difference, disintegration time limit were checked. TLC method was used for qualitative identification. HPLC wavelength switching method was used to simultaneously determine the contents of 3 components with anti-tumor effect, such as epicatechin, camptothecin, and ginsenoside Rb1.
The best preparation process was as following: the dosage ratio of drug to adjuvant was 1∶1.15, the wetting agent (ethanol) concentration was 91%, and drying time was 117 min. The moisture, volume difference and disintegration time limit of the capsule were in line with Chinese Pharmacopoeia. TLC identification is highly specific. The linear ranges of the 3 components with anti-tumor effect were 0.52~16.74 μg·mL-1 (r=0.999 6), 0.68~21.68 μg·mL-1 (r=0.999 9), 6.70~214.49 μg·mL-1 (r=0.999 7), respectively. RSDs of precision, stability and reproducibility tests were lower than 3%. The average recoveries were 97.11% (RSD=1.73%, n=6), 99.33% (RSD=1.68%, n=6), 99.18% (RSD=2.21%, n=6), respectively. The content of them were 0.158 8, 0.196 7, 3.091 3 mg·g-1.
The preparation process of QCC is stable and feasible. The quality control method is comprehensive and systematic.
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