In 2022, the heat index of the whole biomedical industry gradually declined, but the hot track such as gene therapy and cell therapy remains active. Source technology breakthroughs and multidisciplinary cross-integration innovation have accelerated the process of new drug development. There are a rich variety of new drugs approved in 2022, and some blockbuster new drugs and new technology therapies have brought new therapeutic hope for complex diseases. The Center for Drug Evaluation and Research (CDER) of the US FDA approved 37 innovative drugs in 2022, 25 of which were first approved worldwide. The European EMA approved 51 innovative medicines throughout the year, 8 of which were first approved worldwide. Japan's Pharmaceutical and Medical Device Agency (PMDA) approved 48 new drugs throughout the year, 12 of which were first approved in the world. The National Medical Products Administration (NMPA) of China approved 40 new drugs throughout the year, 11 of which were first approved worldwide. This paper summarized the new drugs approved for market in the US, EU, Japan and China in 2022, and provided an outlook on new drug development and biopharmaceutical development trends in 2023.

The novelty examination of pharmaceutical crystal patents often requires the use of legal presumption as a method of finding out the facts. The process is complex because it involves the allocation and transfer of the burden of proof, the refutation and overturn of the presumed facts, and the use of legal techniques in the investigation of technical facts. Through typical cases, this paper compares the differences among different examination procedures in the judgment of evidence that is sufficient to challenge the novelty of pharmaceutical crystals and shift the burden of proof, and explores the reasons for the differences from the perspectives of the uncertainty of crystal acquisition, the purpose and value of the setting of substantive examination and invalidation procedures, the legal status of patents (applications), the burden of proof and the standard of proof, and further analyze the impacts of the presumption methods of different examination procedures and the performance of the parties' request and rebuttal on the grant and stability of the pharmaceutical crystal patent.

Drug regulatory science is a cutting-edge task in the field of drug regulation that has received much attention from the international community in recent years. Currently, different countries and regions have different foundations for drug regulatory industries, are in different stages of development, and face different prominent issues. Therefore, the focus of drug regulatory science and the problems that need to be solved are also different. The origin of drug regulatory science suggests that we should deeply consider the emergence and development of drug regulatory science from the perspective of the arrival of a new era and the emergence of new forces. The definition and characteristics of drug regulatory science suggest that it is a practical science that solves prominent problems and directly serves regulatory decision-making, and future studies should focus on drug regulation rules, develop new regulatory tools, standards and methods, and cultivate new theories, regulations and mechanism.

Based on the new changes in the definition of falsified and substandard drugs and the new requirements for their identification in newly revised "Drug Administration Law" and "Interpretation for Handling the Criminal Cases Endangering Drug Safety", this paper discusses a new working mode for the detection of falsified and substandard drugs. In the new working model, the detection of falsified and substandard drugs can be classified into two kinds: to need and not to need the support of testing results. If testing is needed, three factors should be considered, i.e., the implementer of testing, testing capability, and presentation of testing result. The paper cited two typical examples taking place respectively in 2006 and 2015 to elaborate how testing result supported the detection of falsified and substandard drugs, one is about illegally adding diglycol in injection, another is about adulterated Ginkgo biloba leaves and their extracts. In order to improve the quality and efficiency of the detection of falsified and substandard drugs and optimize the utilization of drug testing resources, the testing of falsified and substandard drugs under the new requirements should be based on the needs of the identification, with the goal of supporting the drug regulatory department to issue the identification opinion about the falsified and substandard drugs. The model will change the traditional understanding on the role of drug testing results in supporting the confirmation of falsified and substandard drugs, to delink the connection between detection and testing, making the testing result not the precondition for the confirmation of falsified and substandard drugs. In order to implement the new work mode, drug regulatory authorities at prefecture level and above need to clarify the identification of whether inspection support is needed according to the laws, national and provincial drug inspection institutions need to establish a division of labor and cooperation mechanism that matches the regulatory functions, and drug testing institutions need to clarify the requirements for samples, standards for testing, and testing conclusion.

Oil APIs for injection extracted from animals and plants mainly used in fat emulsions. Based on the requirements of relevant regulations, guidelines, and review experience in recent years, this paper expounds some considerations on the study of oil APIs for injection extracted from animals and plants, including starting materials and process control, impurity control, validation of virus inactivation/removal process, quality research, etc, in order to provide some references for future research．

Objective: To conduct a research on the current difficulties in the design, evaluation, and implementation of clinical trials of pediatric Chinese medicine and build a list of questions for the development of the Expert Consensus on Issues Related to Clinical Trials of Pediatric Chinese Medicine. Methods: The parties involved in clinical trials of pediatric Chinese medicine were surveyed by online questionnaires to learn the difficulties in the design, evaluation, and implementation of clinical trials. Results: A total of 49 questionnaires were collected, and the experts believed that it was difficult to determine the indications, test purpose, diagnostic criteria, age range, control drugs, efficacy and safety evaluation in the design and evaluation stage of clinical trials of traditional Chinese medicine for children, and there was a lack of scientific basis for developing medication regimen. In the implementation phase, the start time of the trial should be specified, and further improvement should be made in the aspects of ethical review, subject recruitment, informed consent, compliance, and DMC setting. Conclusion: There were many difficulties in the design, evaluation, and implementation of current clinical trials of pediatric Chinese medicines, which should be improved from various aspects such as policy, awareness, and technology, thus to promote the research and development of pediatric proprietary Chinese medicines.

As the use of cell therapy products such as chimeric antigen receptor T cells (CAR-T) is getting matured, there has been an increasing interest in the methods used to test the quality of cell therapy products. In vitro viability assay is an important method for evaluating the effectiveness of cell therapy products and is also widely used in the product release process because of its simplicity and rapidity. In this paper, we review the in vitro potency determination methods for cell therapy products such as CAR-T from the perspective of both effector cells and target cells.

The intake of food could lead to various changes in the physiology of human gastrointestinal tract, such as the pH of the gastrointestinal, ionic strength, buffer capacity, the time of gastric emptying, visceral blood flow, and the metabolizing enzymes. These physiological changes would have effects on the release, absorption, distribution, metabolism, and/or excretion of a drug, leading to changes in its pharmacokinetics. Therefore, it is of great importance for clinical research and prediction of the food effect on novel drugs to understand the manner of change in the luminal condition of human gastrointestinal caused by food intake, as well as the manner of the effect on bioavailability. In this paper, we summarized the clinical trials about the food effect on drugs in clinical trial databases and literature first. Then, the guidelines relevant to clinical trials on food effect issued by the National Medical Products Administration (NMPA) of China, the United States FDA, and EMA were compared and summarized. Finally, taking the antitumor novel drugs as an example, we summarized and analyzed the clinical trials about food effect registered in China in the past 10 years, focusing on the main factors related to the food effect in the development of novel drugs, the official guidelines, as well as the current status of research in China, aiming to provide basic research data about the food effect for the development of novel drugs in China.

Fumagillin is a natural insoluble antibiotic isolated and purified from the liquid fermentation medium of Aspergillus fumigatus. Fumagillin and its derivatives have been found to have a variety of biological activities such as anti-tumor, anti-obesity and anti-microsporidiosis, so they are widely used in the field of medicine. The molecular structure properties, biological activity, application and mechanism of action of fumagillin and its several common derivatives based on C6 site modification, such as fumagillin B, TNP-470, CKD-732 and PPI-2458 are reviewed in this article, and the separation and purification process, activity research and application prospect are prospected in order to provide reference for the further application of low toxic fumagillin and its derivatives in clinical practice and research.

Caffeine is the drug of choice for the treatment of apnea of prematurity. Although it has been used abroad for nearly 50 years, it has only begun to be widely used in China in recent years. There is still no consensus on the timing of caffeine initiation and discontinuation at home and abroad up to now. The efficacy and safety of caffeine under the standard-dose regimen have been confirmed, but the apnea symptoms of some preterm infants are still poorly controlled. The high-dose regimen is more effective, but the potential adverse effects are still worrisome. In addition, the necessity for the therapeutic drug monitoring of caffeine remains debatable since the effective blood concentration range is still controversial. Therefore, the pharmacokinetic characteristics of caffeine in premature infants, as well as the efficacy, safety, and effective blood concentration range under different dosage regimens were summarized. Of note, the research progress of the therapeutic drug monitoring and dose regimen optimization of caffeine were also discussed.

Objective: Drug resistance and endogenous cross-reactivity are the main factors affecting the detection of anti-drug antibody (ADA), so the establishment of method that can tolerate higher drug concentration and avoid endogenous cross-reactivity is a major problem to be solved in immunogenicity analysis. The aim of this study was to establish and verify a method for detection of ADA against recombinant human serum albumin (rHSA). Methods: Anti-rHSA antibody was extracted by acidification and enrichment with magnetic nanobeads and then detected using a bridging method. Finally, the established method was validated. Results: The recovery of the antibody was greater than 80% by using the established method. The sensitivity of the method could reach 0.5 μg·mL^-1 and the intra- and inter-batch RSDs were less than 20%. In addition, the method could resist drug of up to 2 mg·mL^-1. Conclusion: This study established a method for the detection of anti-rHSA antibody. The method has high antibody recovery and good performances of sensitivity and precision. It can also achieve mg-level drug-resistance and effectively remove the interference of endogenous substances, which can be applied for the detection of ADA, extraction of antibody drugs and further analysis of drug metabolism.

Objective: To evaluate the anti-platelet aggregation effect and advantages of Quansanqi tablets (PSQ), an innovative new drug of Panax notoginseng. Methods: Human platelet-rich plasma and washed platelets were used to detect the platelet aggregation rate and calcium ion concentration induced by different platelet activators; rat platelet-rich plasma was used to compare the platelet aggregation rate induced by ADP in PSQ and Panax notoginseng extract; gastric bleeding model rats were established by injecting 80% ethanol to investigate the effects of PSQ and aspirin on fecal occult blood; the hemostatic effect of PSQ was observed by mouse and rat coagulation test. Results: PSQ could dose-dependently inhibit ADP, thrombin, U46619, collagen and reduce anti-CD9-induced human platelet aggregation rate (P<0.01) and Ca²⁺ release (P<0.05 or P<0.01); it could inhibit ADP-induced rat platelet aggregation rate (P<0.01), with significantly better effect than Panax notoginseng extract. PSQ could reduce the fecal occult blood grade in gastric bleeding model rats (P<0.05), while aspirin could not (P>0.05); it could also significantly shorten the coagulation time in mice and APTT time in rats, indicating certain hemostatic effect. Conclusion: PSQ has significant anti-platelet aggregation effect through multiple ways with multiple action targets, and can also reduce the risk of bleeding because of its excellent hemostatic effect, which is a safe and effective new antiplatelet drug.

Objective: To explore the effective compatibility ratio of the 5 main active ingredients in Gardenia and Panax notoginseng by uniform design test method thus to provide preliminary experimental evidence for clinical treatment of Alzheimer's disease. Methods: A model of SH-SY5Y cell injury induced by β-amyloid (Aβ_1-42) was established, and the cell survival rate was used as an indicator to study the effective concentrations of the main active ingredients against Aβ_1-42-induced SH-SY5Y neuronal injury, and according to the damage recovery rate, five ingredients with better efficacy were selected. On this basis, the five components with good efficacy were used as independent variables X₁, X₂, X₃, X₄ and X₅, respectively, the injury recovery rate (%) as the dependent variable Y, U₂₁ (21⁵) uniform design table and 2 mathematical models of linear and quadratic polynomials were selected, and the variables were screened by stepwise regression method to determine the effective compatibility ratio of the 5 active ingredients. Results: The main active components of Gardenia-Panax notoginseng, except genipin, could increase the cell survival rate of SH-SY5Y cells induced by Aβ_1-42 in a concentration-dependent manner. 5 ingredients with good efficacy were identified as notoginsenoside R1, ginsenoside Rb1, ginsenoside Rg1, geniposide, and genipin gentiobiglycoside. The results of uniform design experiments were obtained by regression analysis and Y=12.775 019 92-0.493 827 042 7X₂+0.070 634 665 58X₁X₂-0.022 126 968 533X₁X₅+0.053 000 691 95X₃X₄ (r=0.857 4, F=11.105 9, P=0.002), and the uniform design test verified that the best combination ratio was notoginsenoside R1∶ginsenoside Rb1∶ginsenoside Rg1∶geniposide∶genipin gentiobiglycoside=1∶1∶1∶1∶0. Behavioral experiments showed that compared with the model group, the number of tests and memory errors of donepezil hydrochloride group and gardenia-Panax notoginseng optimal matching were significantly reduced. The results of ROS and Western blot showed that compared with the model group, the optimal combination of donepezil hydrochloride group and gardenia-Panax notoginseng could effectively reduce the fluorescence intensity of ROS and the expression of RAGE protein. Conclusion: The optimal matching ratio obtained by uniform design screening can effectively improve Alzheimer's disease, and its mechanism of action may play an anti-Alzheimer's effect by inhibiting the activation of RAGE-ROS pathway, which provides an experimental basis for the treatment of Alzheimer's disease.

Objective: To study the stability of hepatocyte growth-promoting factor for injection (HGFI) and its compatibility with different material infusion sets by physical and chemical testing and cell experiment. Methods: HGFI was dissolved with different solvents. Then the solution was sampled at 0 h and 24 h with or without infusion tube made of polyvinylchloride (PVC), thermoplastic elastomer (TPE), of thermoplastic polyurethanes (TPU) to determine the pH value, protein, clarity, visible foreign bodies, insoluble particles, osmolarity, content and macromolecular substances. HGFI was dissolved with 5% glucose injection or normal saline for 0 h and 24 h, and then diluted with complete medium and co-incubated with rat liver cells (BRL) for 48 h. The cell viability was detected by CCK-8 method. Results: The pH value, protein, degree of clarification, visible foreign bodies, insoluble particles, osmotic molar concentration, content determination, and macromolecular substances of HGFI dissolved with 5% glucose, normal saline, 5% glucose and normal saline and sampled via/not via infusion tube of different materials (PVC, TPE, TPU) at 0 h and 24 h all met the requirements of 2020 edition of Chinese Pharmacopoeia. Compared with the normal control group, HGFI solutions at 0 h and 24 h not only had no toxic effects on BRL cells, but also significantly increased the viability of BRL cells. Conclusion: HGFI is stable within 24 h with different solvents and has good compatibility with infusion sets of different materials. Moreover, it keeps wonderful bioactivity within 24 h.

Objective: To observe the effect of Xiangpishengji Ointment on the wound surface model of small Bama pigs, preliminarily observe the effect of Xiangpishengji Ointment on the VEGF-Notch signaling pathway in the wound surface of experimental pigs, compare the difference in wound healing between experimental pigs and rodents, and explore the rationality of selecting experimental pigs for the development of wound surface model. Methods: A total of 48 sores were prepared on the back of 4 small Bama pigs and divided into 2 groups, namely the Conwell hydrogel group and the Xiangpishengji Ointment group. Photos were taken on the 0, 7 and 14 days after surgery. Image J software was used to measure the wound area, calculate the wound healing rate, record the wound healing time, and observe the pathological changes with HE staining. The expression of VEGF-Notch signaling pathway related factors in wound tissue was detected by immunohistochemistry. Results: Xiangpishengji Ointment could promote the wound healing of experimental pigs, improve the wound healing rate, shorten the healing time, and promote the expression of VEGF-Notch signaling pathway related factors. Conclusion: Xiangpishengji Ointment can promote the healing of small Bama pig wound model, which may be related to the influence on VEGF-Notch signaling pathway. Experimental pigs are more similar to humans than rats in physiological and pathological aspects, and may become an accurate model for wound healing exploration in the future.