Quality assessment of paediatric randomized controlled trials published in China from 1999 to 2022: a cross-sectional study.

BACKGROUND: Randomized controlled trials (RCTs) are usually the basis of evidence-based medicine, but whether the results of RCTs can be correctly translated into clinical practice depends on the quality of the literature reported. In this study, we evaluated the general characteristics and quality of paediatric RCTs published in China to provide evidence for the reporting of paediatric RCTs and their application in clinical practice. METHODS: We conducted a cross-sectional observational study of paediatric RCTs published in paediatric journals in China between January 1, 1999, and December 30, 2022. All RCTs that included children (younger than 18 years old) were retrieved, and the general characteristics of the RCTs were extracted and analysed. The quality of the RCTs was assessed by the Cochrane quality assessment protocol. RESULTS: After screening 20 available paediatric journals, 3545 RCTs were included for analysis. The average annual growth rate of the number of published paediatric RCTs from 1999 to 2022 was 7.8% (P = 0.005, R2 = 0.311). Most of the studies were carried out in East China [1148 (32.4%]; the centres of the RCTs were mainly single-centre [3453 (97.4%], and the interventions were mainly medication [2442 (68.9%)]. Comparing RCTs published in 2017-2022 with RCTs published in 1999-2004, the quality of RCTs significantly improved in terms of random sequence generation, allocation concealment, blinding participants and personnel, incomplete outcome data and selective outcome reporting. RCTs published in multiple centres from the Chinese Science Citation Database were identified, and the approval of the ethics committee was of better quality for all the analysed risk of bias items. CONCLUSION: The number and quality of paediatric RCTs reported in China have improved in recent years, but the overall quality was relatively low. Special attention should be given to allocation concealment and blinding outcome assessment, and dropouts, adverse effects and sample size calculations should be reported. Promoting government policies, strengthening the standardization of journal publishing and advancing the registration of clinical trials are feasible measures.

Genomic signatures and prognosis of advanced stage Chinese pediatric T cell lymphoblastic lymphoma by whole exome sequencing.

Objective: To investigate the genomic signatures and prognosis of advanced-stage T cell lymphoblastic lymphoma (T-LBL) and to examine the relationship between T-LBL and T cell acute lymphoblastic leukemia (T-ALL). Methods: 35 Chinese T-LBL children with stage III or IV disease were recruited for this study. They were treated with combination chemotherapy and whole exome sequencing. The relationship of the clinical features, prognosis and specific gene mutations was researched. Gene chips of T-LBL and T-ALL were downloaded from a database, and differential gene expression was analyzed. Results: Germline causal gene mutations (CARS or MAP2K2) were detected in 2 patients; 3.06 ± 2.21 somatic causal gene mutations were identified in the 35 patients, and somatic mutations were observed in the NOTCH1, FBXW7, PHF6 and JAK3 genes. NOTCH1 mutations were significantly associated with FBXW7 mutations, and the age at diagnosis of patients with NOTCH1-FBXW7 mutations was less than that of patients without such mutations (P < 0.05). 32 patients achieved complete remission (CR), and 14 and 18 patients were classified into the intermediate risk (IR) group and high risk (HR) group. During a median follow-up of 44 months, 3 patients relapsed. Three-year prospective event free survival (pEFS) was 82.286%, and no significant differences of pEFS were found for different sexes, ages, or statuses of NOTCH1-FBXW7 mutations, (P > 0.05); however, the mean survival time of the IR group was longer than that of the HR group (P < 0.05). Differential expression of genes in the T-LBL and/or T-ALL datasets was analyzed using the R package limma, and 1/3 of the differentially expressed genes were found in both the T-ALL and T-LBL datasets. High expression of PI3K-Akt signal pathway genes and the USP34 gene was found in the T-LBL dataset. Conclusion: Although T-ALL and T-LBL both originate from precursor T-cells and are considered different manifestations of the same disease and the outcome of T-LBL is favorable when using T-ALL-based chemotherapy, there are differences in the gene distribution between T-LBL and T-ALL. It seems that the PI3K-Akt signaling pathway and the USP34 gene play important roles in T-LBL, but medicines targeting the USP34 gene or the PI3K-Akt pathway may be invalid.

Current situation of pediatric clinical trials in China: focus on trials for drug marketing application and administrative approval.

BACKGROUND: Research and development of pediatric drug faces many difficulties and pediatric clinical trials remain a challenge. Since 2011, a series of measures have been taken to encourage research, development of drugs for pediatric patients in China. In this study, we analyzed pediatric clinical trials conducted in China to provide reference for research and development of pediatric drugs and formulation of relevant policies. METHODS: We conducted a cross-sectional observational study of pediatric trials registered in the Drug Trial Registration and Information Publication Platform before Oct. 31, 2021. All trials that recruited children (under 18 years old as defined in China) were retrieved and general characteristics of the trials and the research drugs were extracted and analyzed. The data were extracted and statistically analyzed by excel 2010 and SPSS 22.0, respectively. RESULTS: There were 588 registered pediatric clinical trials, which accounted for 3.94% of the total registered trials. The overall average annual growth rate of the number of trials from 2013 to 2020 was 14.47% (P < 0.01). Of the 588 trials included, there were 312 trials (53.06%) with only children as subjects, 127 trials (21.60%) with research drugs only for children use, and the median of target subject number was 320 with the range of 8 to 600,000. The sponsors and the principal investigators were mainly located in the eastern and northern China. 325 trials were vaccine trials, and the dosage form was mainly injection. There were 98 non-vaccine biological product trials (mainly injections), 135 chemical compound drug trials (mainly tablets), 30 traditional Chinese medicine/natural drugs (mainly granules). Indications of the non-vaccine drugs were mainly diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism. CONCLUSION: The number of pediatric clinical trials in China has increased these years. To further promote pediatric clinical trials and motivate pediatric appropriate drug marketing application and administrative approval, conducting large pediatric clinical trials, further development of dosage forms suitable for children with special attention to neonates and prematurity, and improving uneven geographical distribution of sponsors and researchers are the current challenges.

General characteristics and reasons for the discontinuation of drug clinical trials in mainland China.

BACKGROUND: Although discontinuation is common in clinical trials, no study has been conducted to analyse the current situation and reasons for the suspension or discontinuation of drug clinical trials in China. This study aims to analyse the general characteristics and reasons for the discontinuation of registered clinical trials in mainland China and to identify the associated factors. METHODS: We conducted a cross-sectional observational study of discontinued trials registered in the Drug Trial Registration and Information Publication Platform before March 31, 2020. All trials with a status of terminated or stopped recorded in the platform were classified as discontinued trials and included in the analysis. The basic characteristics of the discontinued trials were recorded, reasons for trial discontinuation were recorded and divided into 4 categories as drug development strategy, trial planning, trial conduct and studied drug. Pearson's chi-square test and fisher's exact test were used to compare the differences in reasons for discontinuation between neoplasm trials and non-neoplasm trials, and to examine the associations of trial characteristics with different reasons related to trials discontinuation. RESULTS: Three hundred twelve discontinued trials were included in this study. The studied drugs were mainly chemical drugs [229 (73.4%)], and indications of the studied drugs were mainly neoplasms [77 (24.7%)]. Geographical location of the discontinued trials were mostly in northern [114 (36.5%)] and eastern [96 (30.8%)] China. Study type of the included trials was mainly bioequivalence studies [97 (31.1%)]. The most common reason for trial discontinuation was commercial or strategic decision [84 (26.9%)], followed by futility/lack of efficacy [70 (22.4%)]. The number of trial centers, sample size and whether participants had been enrolled were significantly associated with trial discontinuation (P <  0.05). Multiple center trials showed a higher rate of trial discontinuation due to trial conduct related reasons than single center trials (P <  0.05), trials with sample size > 500 showed a higher rate of trial discontinuation due to studied drug related reasons (P < 0.05), and trials enrolled participants showed a lower rate of trial discontinuation due to commercial or strategic decision and a higher rate of trial discontinuation due to studied drug related reasons than trials without enrolled participants (P < 0.05). Besides, neoplasm trials showed a higher rate of trial discontinuation due to poor recruitment and safety comparing with non-neoplasm trials (P < 0.05). CONCLUSIONS: Trial discontinuation in China mainly occurred because of commercial or strategic decision and futility/lack of efficacy of the studied drug. Clinical trials with multiple centers and a large sample size may more likely be discontinued due to trial conduct related reasons such as good clinical practice. Discontinuation due to drug safety and lack of efficacy in multiple center trials with a large sample size deserves more attention to avoid resources wastes. Full communication with regulatory authorities such as Center for Drug Evaluation and research institutes to develop a feasible protocol is important for sponsors to avoid trial discontinuation due to protocol issues.

A Chinese Child Presented with Early T Cell Precursor Lymphoblastic Lymphoma.

T cell lymphoblastic lymphoma (T-LBL) is regarded as the leukemic phase of T cell acute lymphoblastic leukemia (T-ALL). The early T cell precursors ALL/LBL (ETP-LBL/ALL) are derived from thymic cells at the ETP differentiation stage and recognized as a high-risk subgroup of T-ALL/LBL. Most of these cases presented with ALL at the disease onset, but the ETP-LBL phase is uncommon. Here, we report a patient who presented with ETP-LBL at the disease onset. In this case, ALL developed even despite receiving chemotherapy, but the patient achieved a complete remission with intensive chemotherapy.

A population pharmacokinetic model for individualised dosage regimens of vancomycin in Chinese neonates and young infants.

Population pharmacokinetic (PPK) modelling is an easy and impartment method for estimating drug concentration for use inindividualized therapy, especially for young patients and to help protect drug-induced diseases. The purpose of this study was to develop a PPK model for effective dosing of vancomycin in Chinese neonates and young infants. The PPK modelling tool Phoenix® NLME™ was use to assess demographic and routine clinical pharmacokinetic (PK) data retrospectively collected for patients admitted to Children's Hospital of Chongqing Medical University between 2011 and 2016. Data of patients admitted to the hospital between January and June of 2017 were used in validation study, and the final model was also preliminary validated in 2 cases in another hospital. A total of 421 serum samples from 316 patients were included in the initial PPK analysis. A two-compartment PPK model was developed, and exponential-error model was used to describe inter-individual variability of clearance. Residual variability was described by an additive model. The final PPK model was demonstrated as valid by internal and external model evaluation. Of note, the clearance and volume of vancomycin in Chinese neonates and young infants may be greater than in Caucasians. Herein, we describe the establishment of an accurate PPK model of vancomycin for Chinese neonates and young infants, which may be useful as a dosing algorithm for this particular paediatric population.

[Clinical features of acute poisoning in hospitalized children: an analysis of 586 cases].

OBJECTIVE: To investigate the clinical features of acute poisoning in hospitalized children. METHODS: A retrospective analysis was performed on the clinical data of 586 hospitalized children who were diagnosed with poisoning and discharged from the Children's Hospital of Chongqing Medical University between January 2006 and December 2015. RESULTS: The patients included 354 males and 232 females (age: 24 days to 15.8 years). Of the 586 cases, 450 (76.8%) were infants and preschool children; 463 (79.0%) came from rural areas; 551 (94.0%) were hospitalized because of unintentional poisoning. The drug poisoning, pesticide poisoning, and rodenticide poisoning accounted for 221 cases (37.7%), 167 cases (28.5%), and 175 cases (29.9%) respectively. There was a significant difference in the distribution of the poisoning toxins between urban and rural children (P<0.01), and drugs and pesticides were the most common toxins for urban and rural children respectively. There were significant differences in main clinical manifestations between the children with drug poisoning, pesticide poisoning, and rodenticide poisoning (P<0.01), who presented with main clinical symptoms of the nervous system, digestive system, and circulatory system respectively. There was no significant difference in overall response rate between the children poisoned by different toxins. CONCLUSIONS: Acute poisoning is most common in infants and preschool children. The majority of the patients are from rural areas. The majority of acute poisoning is unintentional. Poisoning by drugs is the main type of acute poisoning. There is no significant difference in overall response rate between the children poisoned by different toxins, but their clinical manifestations are different.