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.

With the boom of China's innovative pharmaceutical industry, licensing-in model has gradually become an important research and development model for innovative pharmaceutical companies. The in-licensed drugs at different stages need different research and development (R&D) strategy in China. The pharmaceutical companies take the responsibility to comprehensively collate the oversea clinical data and conduct a detailed analysis of clinical pharmacology, safety, efficacy and ethnic sensitivity. Clinical R&D strategy should be made based on the results of the above data and analysis. We encourage high-quality drugs which fill unmet clinical needs licensed in, and as early as possible, so as to conduct multi-regional clinical trials (MRCTs). The clinical R&D strategy in China is particularly important for the drug's approval. Guidelines published by the National Medical Products Administration (NMPA) and clinical associations should be followed. Communications about clinical R&D strategy with Center of Drug Evaluation (CDE) are encouraged.
.
Antineoplastic Agents/therapeutic use* ; China ; Drug Industry ; Humans ; Lung Neoplasms/drug therapy* ; Pharmaceutical Preparations

Hemophilia is the only rare hereditary hemorrhagic disorder included in the First Rare Diseases catalogue. However, rare bleeding diseases identified in the clinic are far more common than hemophilia. Most other rare hemorrhagic disorders have less effective treatment than hemophilia. Hemophilia has a history of successful drug development in rare hemorrhagic diseases, and the cycle between clinical research and drug development has been gradually realized. Drug research and pharmaceutical companies can refer to the drug research and development process in the field of hemophilia, learn from the experience of hemophilia drug research and develop treatments. The industry can increase drug development by strengthening basic research, focusing on the value of natural history research, the application of quantitative pharmacological tools and improving the efficiency of drug development to meet the urgent unmet medical needs of patients with rare hemorrhagic diseases.

Objective To investigate the effects of shoes type (barefoot, ordinary running shoes, minimalist shoes) and walking speed (jogging, walking at normal speed) on biomechanical parameters of knee joint, so as to provide theoretical reference for scientific fitness. Methods Vicon three-dimensional （3D） motion capture system and Kistler 3D force plate were used to collect biomechanical parameters of lower limbs from 10 subjects during walking at different speed with different shoes. Two-way (2 walking conditions × 3 shoe conditions) repeated measures analysis of variance was used to statistically analyze each dependent variable. Results Compared with jogging, the lateral excursion of plantar center of pressure (COP) was greater, the moment arm in frontal plane, the adduction moment and peak loading rate of knee joint were smaller, but the angular impulse of knee joint in frontal plane was greater. Compared with ordinary running shoes, the stride length was decreased, the lateral excursion of COP was greater, and the moment arm of knee joint in frontal plane, the knee adduction moment, the peak load rate and the angular impulse of knee joint in frontal plane were smaller. Conclusions In order to reduce the angular impulse and peak loading rate of knee joint in frontal plane, it is recommended to jog with small strides for ordinary people with minimalist footwear.

Objective:To explore the effect of Chin-down-plus-larynx-tightening maneuver on improving choking cough and swallowing function in patients after esophageal cancer surgery.Methods:A total of 121 patients with esophageal cancer surgery had been randomly divided into control group and observation group from November 2018 to September 2019. Starting from feeding after surgery, the head and neck were in normal habits when swallowing in the control group, and the observation group used Chin-down-plus-larynx-tightening maneuver to perform swallowing training. The feeding process of two groups was observed and recorded for one week. One week after eating, the water swallowing test and M. D. Anderson Symptom Inventory for Gastrointestinal cancer (MDASI-GI) were used to evaluate the difference of swallowing function and gastrointestinal symptoms between the two groups.Results:During one week period of feeding, the incidence of choking cough in observation group was 3.39%, (2/59), which was significantly lower than that in the control group (14.52%, 9/62)( χ2 value was 4.53, P=0.033). After one week of feeding, the swallowing function showed significant difference ( Z value was 6.07, P=0.014), the gastrointestinal symptoms and the degree of life interference caused by gastrointestinal symptoms of observation group scored 2.57 ± 0.81, 1.76 ± 0.84, lower than those of the control group (4.25 ± 1.54, 2.18 ± 1.24), and the difference was statistically significant( t values were -7.56, -2.17, P<0.05). Conclusions:The Chin-down-plus-larynx-tightening maneuver can promote recovery of postoperative swallowing function in patients with esophageal cancer, reduce the incidence of choking cough, and help reduce the symptoms of digestive tract, and then raise the level of patient′s clinical prognosis.

Objective:To explore the influencing factors of discharge readiness of patients after radical resection of esophageal cancer under enhanced recovery after surgery (ERAS) model and to explore the prediction model.Methods:Using the convenient sampling method, a total of 195 patients with esophageal cancer who were admitted to the department of thoracic surgery in a hospital in Henan Province from January 2019 to April 2020 were selected as the research objects. At discharge, the general and disease-related data collection form, Readiness for Hospital Discharge Scale, M.D.Anderson Symptom Inventory Gastrointestinal (MDAS-GI) , Frail Scale, Time Up and Go Test (TUGT) and Water Swallow Test were used to investigate. Multivariate unconditional Logistic regression analysis was used to analyze influencing factors.A total of 195 questionnaires were distributed in this study, and 189 valid questionnaires were collected.Results:Plasma albumin level, 24-hour food intake, MDASI-GI and TUGT were independent predictors of the readiness for discharge of patients after radical resection of esophageal cancer ( P<0.05) . Finally, the prediction model of postoperative discharge readiness for patients was Y=-3× X1+1× X2+5× X3-4× X4-1× X5 ( Y=discharge readiness; X1=pain score, X2=plasma albumin, X3=24 h food intake, X4=MDASI, X5=TUGT) . Conclusions:The readiness for discharge of patients with esophageal cancer under the ERAS mode is affected by many factors, and the prediction model of discharge assessment is effective, which can provide reference for clinical discharge decision-making.

Objective: To study the response characteristics of the posterior intralaminar nucleus (PIN) of auditory thalamus in VGluT2-Cre transgenic adult mice when exposed to white noise and 10K pure tone stimulation. Methods: All adult male Vglut2-Cre mice (8-12 weeks) were used in this study between Oct, 2017 and Oct, 2018. Using the calcium signal fiber photometry method, optic fiber was employed to locate on PIN by injecting AAV-hSyn-DIO-GCaMP6m virus, and thereafter, the activity of the target cluster neurons during different acoustic stimuli was recorded. Matlab was used for data processing and statistical analysis. Results: (1)In both white noise and 10 kHz pure tone as a continuous three-second stimulation, the peak amplitude of calcium signal activity generated in PIN by white noise was superior to that of pure tone, the statistic result showed significantly difference (n=6, t=2.404, P=0.037 1) . (2)In addition, when white noise and 10K pure tone played as consecutive 3 or 5 pips within three-second stimulation, the stimulus-following ability in a consecutive 3 pulses play within 3 seconds was far better than a consecutive 5 pips play within 3 seconds (in both white noise and 10 kHz pure tone), yet consecutive 3 pips play showed greater signal attenuation speed than that in consecutive 5 pips play, the statistic result showed significantly difference (n=6, t=2.748 P=0.033 4) .(3)Regardless of the intra-group comparisons between white noise and 10 kHz pure tone stimulation, PIN showed better signal response in a consecutive 3 pips play than consecutive 5 pips play or a continuous three-second stimulation. When came to the statistical analysis, the acoustic response degree of a continuous three-second stimulation was an intermediate between two others, both consecutive 3 or 5 pips play showed significantly difference. Conclusions The results suggest that under the same acoustic intensity, VGluT2-Cre transgenic adult mice′s PIN shows greater signal response in white noise than pure tone. PIN shows greater signal attenuation to repetition play of 10 kHz pure tone, which implies PIN shows stronger adaptation to 10 kHz pure tone than to white noise. Lastly, PIN is more responsive to a complex sound information (white noise) than to simple sound information (pure tone).

Objective To observe the effect of air mattress bed on the quality of chest compression during cardiopulmonary resuscitation (CPR). Methods This was a self-controlled study and included twenty formally CPR-trained doctors. According to the 2015 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care, chest compression was randomly tested on a manikin for two minutes in A, B, C group. Group A was tested in ordinary bed, group B was compress in air mattress and hard backboard, and group C was tested in air mattress bed. There was a ten minutes rest between each compression. All compression data, including compression rate, depth, incomplete recoil and shallow number, were collected via real-time feedback device. Statistical analysis was performed using SPSS 22.0. Multiple groups were compared with One-way ANOVA and within groups were compared with t test. The enumeration data was analyzed by chi-square test. Results There was no statistically significant difference between groups in mean chest compression rates (107.9±5.1 vs. 107.7±4.56 vs. 109.7±4.86, P=0.6). Mean compression depth was significantly better in group A and B than in group C [(53.45±2.04) mm and (52.65±2.13) mm vs. (48.45±1.36) mm, all P<0.05)]. The number of shallow compression in group C was significantly higher than those in group A and B [(97.3±23.4) vs. (23.6±19.3) and (35.3±33.9), all P<0.05)]. The retention rates in group A was better than those in group B and C [(58.43±4.17％) vs. (62.51±4.37)％ and (62.63±4.22)％, all P<0.05]. The compression depth of group C in the second minute was significantly less than that in the first minute (46.45±1.43 mm vs. 50.05±1.64 mm, P<0.05), and the number of shallow compression was more than the first minute (62.1±16.4 vs. 35.3±8.5, P<0.05). Significant difference in accuracy was observed among the three groups (33.64％ vs. 28.66％ vs. 19.24％, P<0.05). Conclusions The use of air mattress bed in CPR has a significant impact on the quality of manual chest compression. Eliminating the elasticity of air mattress bed would effectively improve the quality of chest compressions.

Objective To establish a mouse model of 5-fluorouracil ( 5-FU )-induced intestinal mucositis. Methods Different doses of 5-FU were intraperitonealy injected into mice for once or 5 consecutive days. The body weight and diarrhea score of the mice were recorded every day, and peripheral blood and the morphological changes of small intestine were examined at 24 h or 72 h after the last 5-FU administration. Results Compared with the control group, after administered 5-FU, the dosage groups showed various degrees of body weight loss and diarrhea, and the white blood cell and platelet counts in peripheral blood decreased significantly (P＜0. 05 or P＜0. 01). The small intestine showed evident pathological changes after the single dose 400 mg/kg and the continuous injection of 50 mg/kg, 100 mg/kg. The mortality rate was 100% in the 100 mg/kg group. Conclusions A mouse model of intestinal mucositis can be successfully established by a single injection of 5-FU or for consecutive 5 days, in a dose-dependent manner. The optimal dose for single injection is 400 mg/kg, and that of the continual injection for 5 consecutive days is 50 mg/kg.

Objective To investigate the protective function of endovascular cooling method on post-resuscitation syndrome (PRS) in porcine cardiac arrest (CA) model and its mechanism.Methods Ventricular fibrillation (VF) was electrically induced and untreated for 8 minutes in 15 healthy male porcines, cardiopulmonary resuscitation (CPR) was then initiated. All successful recovery animals were randomly divided into two groups by random number table. In normal temperature group, the core temperature was maintained at (38.0±0.5) ℃ for 12 hours. In mild hypothermia group, the mild hypothermia treatment was initiated at 5 minutes after successful resuscitation, the treatment of rapid endovascular cooling was performed to reach the target cooling temperature of (33.0±1.0) ℃, and then maintained until 6 hours after resuscitation. Rewarming was implemented at the rate of 0.7 ℃/h until the body temperature reached (38.0±0.5) ℃. Hemodynamic parameters including heart rate (HR), mean arterial blood pressure (MAP), cardiac output (CO) were continually monitored. Right femoral vein blood was collected before VF and 1, 2, 4, 6, 12 and 24 hours after resuscitation, respectively, and the serum concentrations of E-selectin, soluble thrombomodulin (sTM), and interleukin-1β(IL-1β) were determined with enzyme linked immunosorbent assay (ELISA). The survival of porcines at 24 hours after resuscitation was observed, and the neurological deficit score (NDS) was calculated for the surviving porcines. All animals were sacrificed, and brain, heart and lung tissues were collected, after hematoxylin and eosin (HE) staining, the histopathology changes were evaluated under a light microscopy.Results After 8-minute VF, 14 porcines were resuscitated successfully, 7 porcines in normal temperature group and 7 in mild hypothermia group respectively, with the resuscitation success rate of 93.3％. There was no significant difference in body weigh, core temperature, hemodynamics, or blood lactate as well as duration of CPR and the number of defibrillations between the two groups. The core temperature of normal temperature group was maintained at (38.0±0.5) ℃, while in mild hypothermia group, the hypothermia was reduced to the hypothermia range (33.0±1.0) ℃until 6 hours, then rewarmed to normothermia gradually [(38.0±0.5) ℃]. Compared with those before VF, HR was significantly increased after resuscitation in both groups, and MAP and CO were decreased, then they tended to normal. There was no significant difference in hemodynamic parameter at all time points between the two groups. Compared with those before VF, the levels of E-selectin and sTM in serum of the two groups were increased significantly at 1 hour after resuscitation, and they were decreased gradually after reaching the peak at 6 hours, and IL-1β was increased continuously with time. There was no significant difference in E-selectin (μg/L:1.34±0.52 vs. 1.60±0.61), sTM (μg/L: 19.13±0.34 vs. 19.24±0.73), or IL-1β (ng/L: 25.73±0.87 vs. 25.32±0.25) before VF between normal temperature group and mild hypothermia group (allP> 0.05). The levels of E-selection, sTM and IL-1β in mild hypothermia group were significantly lower than those in normal temperature group from 2 hours after resuscitation [E-selection (μg/L): 11.15±2.73 vs. 16.04±3.23, sTM (μg/L): 49.67±3.32 vs. 62.22±1.85, IL-1β (ng/L): 140.51±6.66 vs. 176.29±18.51, allP< 0.05], and E-selection decreased to the baseline level at 12 hours (μg/L: 1.17±0.65 vs. 1.60±0.61,P > 0.05). The 24-hour survival rates of two groups were both 100％. The NDS score of mild hypothermia group was obviously lower than that of normal temperature group (150.0±6.6 vs. 326.4±12.3,P < 0.05). In normal temperature group, neuronal cell necrosis was observed in the cerebral cortex at 24 hours after resuscitation, and nucleus was deeply stained. The myocardial necrosis and alveolar collapse was found. Meanwhile the infiltration of inflammatory cell could be found in the myocardium and alveolar. The brain, lung and myocardium injury were significantly milder in mild hypothermia group as compared with those in normal temperature group.Conclusions The intravascular cooling therapy was a safe and effective method for inducing mild hypothermia after resuscitation. This cooling effect was fast and reliable, and the rewarming speed was controllable and stable. The protective mechanism of mild hypothermia on PRS may be related to inhibiting systemic inflammatory response and reducing vascular endothelial cell injury.