Analysis of constraints and policy recommendations for the development of pediatric drugs in China:Based on the perspective of pharmaceutical enterprises / 中国卫生政策研究

Objective:To provide a basis for improving the design and implementation of policies for ensuring the supply of pediatric drugs in China.Method:Based on the perspective of pharmaceutical enterprises,reviewed literature and conducts questionnaire surveys to identify the constraints in the development of pediatrict drugs throughout the entire drug lifecycle,and analyzes the constraints'concentration and urgency.Result:The main constraints include:difficulty in conducting clinical trials for children;the current registration and approval rules lack consideration for the specificity of pediatric drugs and specific requirements for application materials;lack of implementation rules and measures in the implementation process of incentive policies for pediatric drug production;The market interest mechanism of pediatric drugs is not yet perfect.Among them,research and development and payment for use are currently relatively concentrated issues.Discussion and suggestions:It is recommended that China fully utilize existing clinical trial data of pediatric and broaden sources,take multiple measures to increase investment in pediatric drug R&D;Develop special guidelines for pediatric drug application and encourage adult drug registration to submit pediatric research plans;Explore the optimization path of pediatrict drug production and supply based on typical cases;Provide more space for pediatric drugs in the rules of drug use and payment.

The Effects of Different Pediatric Drugs and Brushing on the Color Stability of Esthetic Restorative Materials Used in Pediatric Dentistry: An In Vitro Study.

The aim of the current study is to observe how different pediatric drugs and tooth brushing affect the color stability of different esthetic restorative materials. Three restorative materials (composite, compomer, and glass ionomer cement (GIC)) were each used to produce 72 specimens (10 mm × 2 mm). The specimens were divided into six groups and immersed in distilled water and five different pediatric drugs (amoxicillin, ibuprofen, ventolin, paracetamol, and multivitamins). Each group was divided into two subgroups (brushed and non-brushed). Over the course of two weeks, the specimens were agitated for one minute every eight hours. Color changes in all the specimens were evaluated using a spectrophotometer at 1 and 2 weeks. GIC showed a change in color that was significantly greater than that in all the other materials in each solution, except for those in amoxicillin. After a period of 1 to 2 weeks, the most noticeable change in color was detected in the amoxicillin composite and amoxicillin GIC unbrushed groups, and after 2 weeks, a significant difference was found in the ventolin GIC unbrushed group. The color stability of the restorative materials used in pediatric dentistry can be influenced by using popular liquid pediatric medications. GIC was the least color-stable material when subjected to liquid medications.

US Food and Drug Administration Facilitated Pediatric Approval Programs: Application to Pediatric Neurological Disorders.

Crucial time is often lost while waiting for approval of therapies for pediatric neurological disorders, many of which have aggressive manifestations with devastating effects. There are logistical, ethical, and financial impediments that face the studies needed to determine efficacy and safety of therapies in children. In this article, the authors present the Food and Drug Administration's programs aimed at facilitating the development of pediatric drugs, focusing on their application to pediatric neurological disorders. They also provide examples of drugs that received, or are currently enrolled in, these programs. Reflecting upon the commonalities of drugs receiving these designations, the authors highlight underlying ethical issues related to pediatric drug development and emphasize the need for structured incentives to stimulate approval and production of drug therapies for pediatric neurology patients. By consolidating information that applies to drug approval of pediatric neurological disorders, stakeholders in drug development can enhance treatment development for these disorders.

Systematic Data Monitoring and Analysis of Cardiovascular Off-label Prescriptions in Pediatrics: Focus on Angiotensin-Converting Enzyme Inhibitors (ACE-I) and Beta Blockers.

INTRODUCTION: Many efforts have been made to stimulate clinical trials (CTs) in pediatrics but most of the drugs are still authorized only in adults and used off-label in the pediatric population. AIM: To assess how widespread is the off-label prescription in Italy and to identify areas of unmet medical need by applying a model for the systematic collection and analysis of data. METHODS: A study was performed using 2015 data from the Italian Medicines Utilization Monitoring Centre Health Database (OsMed). A study sample of 3,726,583 pediatric patients, was considered. Cardiovascular drugs were selected for this study. Assessment of the off-label use, the analysis of the pharmacovigilance signals, a bibliographic research and the analysis of ongoing CTs were carried out. RESULTS: In 2015, 8,544 pediatric patients received treatment with a cardiovascular drug. Angiotensin converting enzyme inhibitors (ACE-I) followed by beta blockers agents are the most prescribed molecules. Eight molecules were selected and an in-depth analysis conducted. The PhV network showed only one record of adverse reaction as off-label in 2015. The results show several therapeutic areas of use in pediatrics. CONCLUSION: Off-label in pediatrics is largely widespread in Europe and US and our results show it is also present in Italy. Molecules selected are used off-label for therapeutic areas such as oncologic, hematological and rare diseases. Results of pharmacovigilance suggests underreporting. The analysis carried out in this study could be an open track for a systematic monitoring activity and of interest for prescribers, pediatricians and other healthcare professionals during the clinical practice.

Model-Informed Optimization of a Pediatric Clinical Pharmacokinetic Trial of a New Spironolactone Liquid Formulation.

Quantitative pharmacology brings important advantages in the design and conduct of pediatric clinical trials. Herein, we demonstrate the application of a model-based approach to select doses and pharmacokinetic sampling scenarios for the clinical evaluation of a novel oral suspension of spironolactone in pediatric patients with edema. A population pharmacokinetic model was developed and qualified for spironolactone and its metabolite, canrenone, using data from adults and bridged to pediatrics (2 to <17 years old) using allometric scaling. The model was then used via simulation to explore different dosing and sampling scenarios. Doses of 0.5 and 1.5 mg/kg led to target exposures (i.e., similar to 25 and 100 mg of the reference product in adults) in all the reference pediatric ages (i.e., 2, 6, 12 and 17 years). Additionally, two different sampling scenarios were delineated to accommodate patients into sparse sampling schemes informative to characterize drug pharmacokinetics while minimizing phlebotomy and burden to participating children.

Elemental Impurities in Pediatric Calcium Carbonate Preparations-High Throughput Quantification and Risk Assessment.

Calcium carbonate which is extracted from the Earth in combination with other mineral impurities, is largely used in preparations for pediatric supplements. Elemental impurities in drug products pose toxicological concerns without therapeutic benefits. Thus, it is very urgent to assess the safety of chronic exposure to elements that may be present in trace amounts. In the present study, we developed high throughput ICP-MS method for the quantitative determination of 62 elemental impurities in high matric calcium carbonate samples and validated according to USP 233. Calcium carbonate preparations which state clearly used for child (including neonates, infants, toddlers and children) from 9 manufactures and two types of raw materials (light calcium carbonate and ground calcium carbonate) were investigated in terms of the content and variability of 62 elemental impurities. According to the results, ground calcium carbonate was more suitable to be used in pediatric preparations concerning elemental impurities. Parts of elemental impurities in CaCO3 preparations which are derived from the raw materials and the preparation process, may cause potential risks for children. These results indicate that it is necessary to establish a modern instrumental analysis method to evaluate and control elemental impurities in CaCO3 raw materials and preparations.

Analysis of the Marketing Approval of Pediatric Drugs in the United States and Its Enlightenment to Pedia tric Drug Use Guarantee in China / 中国药房

OBJECTIVE：To provide sugge stions for improving the variety of pediatric drugs and ensuring the safety of pediatric drug use in China. METHODS ：The historical evolution of laws and regulations on the marketing approval of pediatric drugs in the United States and the implementation results of relevant policies were summarized. Combined with the current situation of the development of pediatric drugs in China ，some suggestions were put forward to ensure the accessibility and safety of pediatric drug use in China. RESULTS & CONCLUSIONS ：Since 1994，the United States had issued a series of laws and regulations to encourage the development of pediatric drugs. At present ，the marketing approval of pediatric drugs were mainly based on the two laws of Best Pediatric Drug Act（BPCA）and Pediatric Research Equality Act （PREA）. From 1998 to 2019，the amount of supplements of pediatric drug information in drug instructions of the United States showed a fluctuating growth. As of April 2020，854 kinds of drugs had been modified in pediatric instructions ，792 of which had been carried out post marketing pediatric clinical research ，and the problem of incomplete pediatric instructions had also been greatly improved. At present ，China’s policies on pediatric drugs mainly included encouraging R&D innovation ，giving priority to review and approval ，and strengthening R&D technical guidance. Although certain achievements had been made ，there were still some problems ，such as imperfect policies and regulations ，and great difficulties carrying out pediatric drug clinical trials. It is suggested that our country should draw lessons from the American regulations on pediatric drugs ，pediatric research and the catalogue of pediatric drugs ，and establish a system and catalogue of ped iatric drug use suitable for China ’s national conditions ，so as to improve the effectiveness ，safety and accessibilityof pediatric drugs.

Pediatric Drug Pricing and Price Incentive Policy in Japan and Its Enlightenment to China / 中国药房

OBJECTIVE：To learn from pedia tric drug pricing and price incentive policy in Japan ，and to provide reference for the improvement of pediatric drug price system in China. METHODS ：The drug pricing strategy of Japan was analyzed ，and price incentive policy of pediatric drugs in Japan and its implementation status and effect were summarized. The suggestions of perfecting the price system of pediatric drugs in China were put forward . RESULTS & CONCLUSIONS ：The pricing strategy of medical insurance drugs in Japan included two types ，such as access pricing of medical insurance list and price adjustment of drugs in medical insurance list. Among them ，price incentive policy for pediatric drugs mainly included the premium for initial pricing of new pediatric drugs ，the premium for drugs with newly added pediatric indication included in medical insurance list and other measures（such as eligible drugs could obtain indirect price compensation ，and children ’s factors could be considered in health technology assessment ）. Overall ，these measures accelerated the R&D and marketing of Japanese pediatric drugs ，and effectively promoted the development of pediatric drugs in Japan. The author suggests that our country should carry out health technology assessment which reflects the particularity of pediatric drugs ，give appropriate direct price incentives to the payment price of pediatric drugs ，and reasonably set the price of drug specification suitable for children and give price incentives so as to promote the development of pediatric drugs in China.

Effects of different pediatric drugs and toothbrushing on color change of restorative materials used in pediatric dentistry.

OBJECTIVE: The purpose of this study was to evaluate the effects of different pediatric drugs and toothbrushing on color changes of restorative materials used in pediatric dentistry. MATERIALS AND METHODS: Sixty specimens were prepared from each of three restorative materials (compomer [Dyract XP], glass hybrid [Equia Forte], and glass carbomer [GCP Glass Fill]). Specimens were divided into six solution groups (n = 10) and immersed in five different pediatric drugs (antibiotic, analgesic, common cold syrup, cough syrup, and an iron and vitamin formula) and distilled water. Two subgroups (brushed and unbrushed) were established for each group (n = 5). Specimens were agitated for 1 min every 8 h over 2 weeks. Color changes [CIEDE2000 (ΔE00)] were calculated at baseline, 7, and 14 days. Data were subjected to 4-factor mixed-design ANOVA using a general linear model procedure for repeated measurements. RESULTS: After 14 days, the highest ΔE00was found in the compomer/non-brushing group immersed in iron and vitamin formula (5.6 ± 0.27), and the lowest was in glass hybrid/brushing group immersed in distilled water (0.59 ± 0.8) pairwise. ΔE00values were significantly greater for compomer than for glass hybrid or glass carbomer (P < 0.05). There were statistically significant differences between the brushing and non-brushing groups for all tested solutions on the compomer specimens (except antibiotic) and glass hybrid specimens (except antibiotic and cough syrup). The Δ00 values in brushing groups were significantly lower statistically than in non-brushing groups (P < 0.05). CONCLUSIONS: Toothbrushing dramatically affected the color stability of the aesthetic restorative materials. The content of pediatric drugs is also an important factor for color change. Glass hybrids and glass carbomers used with their surface sealants appeared to be more resistant to staining from pediatric drug formulations than compomers.

Usage and Dosage of Kaihoujian Throat Spray (for Children) in Treatment of Acute Pharyngitis and Acute Tonsillitis / 中国实验方剂学杂志

Objective:To explore the effective dose range of Kaihoujian throat spray (for children) in treating acute pharyngitis and acute tonsillitis, in order to provide the reference for the usage and dosage in clinic. Method:A total of 160 juvenile SD rats were divided into 16 groups according to the body mass grade, namely normal group, model group, amoxicillin or ribavirin group, compound Yizhi Huanghua group and different doses of Kaihoujian (for children) groups. The different doses of Kaihoujian (for children) groups were divided into 12 treatment groups based on 2 sprays/time, 4 times/day, 4 sprays/time, 4 times/day, 6 sprays/time, 4 times/day, 8 sprays/time, 4 times/day, 2 sprays/time, 6 times/day, 4 sprays/time, 6 times/day, 6 sprays/time, 6 times/day, 8 sprays/time, 6 times/day, 2 sprays/time, 8 times/day, 4 sprays/time, 8 times/day, 6 sprays/time, 8 times/day, and 8 sprays/time, 8 times/day. Except for normal group, all of the remaining groups were included in three animal models, namely 5%ammonia-induced acute pharyngitis in rat, B type streptococcus haemolyticus-induced acute pharyngitis and tonsillitis in rabbit, and adenovirus-induced acute pharyngitis in mice. Then the optimal usage and dosage of Kaihoujian throat spray (for children) were evaluated based on pharyngeal lesion score and htoxylin eosin(HE) staining. Result:There were significant differences in pharyngeal and tonsil lesions between the model group and the normal group (PPPConclusion:The clinical usage and dosage of Kaihoujian throat spray (for children) in treating acute pharyngitis and tonsillitis were suggested to be 2 sprays/times, 6~8 times/day for 1~3 year-old children; 3~6 sprays/times, 6~8 times/day for 4~6 year-old children and 5~8 sprays/times, 6~8 times/day for 7~12 year-old children.

Bitterness prediction in-silico: A step towards better drugs.

Bitter taste is innately aversive and thought to protect against consuming poisons. Bitter taste receptors (Tas2Rs) are G-protein coupled receptors, expressed both orally and extra-orally and proposed as novel targets for several indications, including asthma. Many clinical drugs elicit bitter taste, suggesting the possibility of drugs re-purposing. On the other hand, the bitter taste of medicine presents a major compliance problem for pediatric drugs. Thus, efficient tools for predicting, measuring and masking bitterness of active pharmaceutical ingredients (APIs) are required by the pharmaceutical industry. Here we highlight the BitterDB database of bitter compounds and survey the main computational approaches to prediction of bitter taste based on compound's chemical structure. Current in silico bitterness prediction methods provide encouraging results, can be constantly improved using growing experimental data, and present a reliable and efficient addition to the APIs development toolbox.

Key technologies of clinical study of traditional Chinese medicine on pediatric functional abdominal pain / 药物评价研究

Functional abdominal pain is one of the most common problems in functional gastrointestinal disorders,and it's also one of the diseases benefit most from traditional Chinese medicine (TCM) treatment.This paper illustrates some key considerations on the study design of traditional Chinese medicine intended for the treatment of FAP based on the latest treatment and evaluation guidelines,technical guidance,professional authority works as well as the latest clinical studies,and combined with experience of clinical trial design.It hopes to offer helps for research designers in this genera.

Determination of parameters of developmental toxicity study on pediatric drugs and focus of attention for safety evaluation of traditional Chinese medicine / 中国药理学与毒理学杂志

There is an increasing demand for neonatal and juvenile animal toxicity studies during the research and development of new drugs. In this paper,we discussed general evaluation parameters of pediatric non-clinical safety with pediatric drugs,such as growth and development and food intake,and paramenters of other organs and systems, such as the central nervous system,reproductive system, behavior evaluation in combination with our own experience. In addition,the characteristics of non-clin?ical safety evaluation of new traditional Chinese medicine materia medica used for juvenile animals were analyzed. This paper is intended reference for non-clinical safety evaluation of pediatric drugs and to gain some experience related to formulation of new guidelines.

Comparisons of the 2015 edition of WHO model list of essential medicines for children and the 2012 edition of list of national essential medicines for children / 国际药学研究杂志

This study focuses on comparing the 2015 edition of WHO model list of essential medicines for children with the 2012 edition of list of national essential medicines for children in respects of drug categories,dosage forms,specifications and medica?tion information. The number of essential medicines available for children in China roughly equals to that of WHO model list of essen?tial medicines for children. Though China′s list provides more specific and children-agreeable specifications,it lags behind the WHO list with respect to the number of dosage forms and information concerning pediatric weight limitation ,drug combination and alterna?tives. It is recommended that research and development on dosage forms for children should be strengthened to solve the problem of pe?diatric drugs shortage. Also,more clinical trials should be developed as supporting evidence. Based on adapting to the needs of basic health services of children,essential medicines list for children in China should be established.

Pediatric drugs in China:problems and countermeasures / 国际药学研究杂志

Taking the differences between the pediatric drugs and adult drugs as the starting-point,this article analyzes the main problems of the pediatric drugs in China,such as the shortage of the pediatric drugs. The causes of the problems mainly include high research and development cost of the pediatric drugs,their limited market capacity,difficulty in recruiting trial participants,the less clinical trial institutions in pediatrics,and governments′incentive polices on research and development of pediatric drugs did not really play their roles. The countermeasures to solve these problems mainly include introducing relevant policy to guarantee the re?search and development companies′profit,selecting appropriate varieties of the pediatric drugs to research and develop,promoting the establishment of pediatric clinical trial institutions as soon as possible,and establishing particular passage for pediatric drugs ap?proval,in order to provide references for the government when making policies on pediatric drugs.

Comparison of the regulation of pediatric drugs research and development at home and abroad / 国际药学研究杂志

The problem of pediatric drugs has been the challenges facing the world. The two most important issues are the lack of appropriate drug dosage forms for children and the safety and effectiveness data of drug use in children. How to encourage produc?tion enterprises to produce drug varieties,specifications and dosage forms suitable for children use,guide drug manufacturers to ob?tain drug use data are the most important work for pediatric drugs.Based on the literature home and abroad,we analyze the regulatory policies for the research and development(RD)and application of pediatric drugs in the USA,EU and Japan,which have made great efforts to encourage enterprises to conduct pediatric research. Their successful experiences are summarized and can be used as refer?ence for the establishment of the policies adaptive to the situation of China for the RD of pediatric drugs.

Overview of China′s pediatric drug situation and regulatory policy / 国际药学研究杂志

Pediatric drug accessibility has become a global problem,pediatric drug shortages and off-label uses are very seri?ous. In China,lack of suitable varieties,appropriate dosage forms and specifications,weak foundations on clinical trials,irregular prescribing behavior and irrational drug use and other issues on pediatric drugs are still outstanding. To improve pediatric drug accessi?bility,it may need all aspects work together,that is,cooperation of the national macro-policy support,participation of enterprises and medical institutions,to establish realistic goals and programs to address pediatric drug problem. This paper studies the foreign pediat?ric regulation measures and policies and by comparing foreign policies to China′s current situation,we can find out the problems and defects,give appropriate advice,in order to provide advice and reference to promote the development of pediatric drug.

Orally disintegrating tablets based on lyophillization technology:research advances / 国际药学研究杂志

The orally disintegrating tablets(ODT)are the kinds of novel oral dosage forms which begin to gain popularity and acceptance since they can disintegrate/dissolve quickly in the oral cavity upon contact with saliva ,resulting in solutions or suspensions form of the administered medicine. The ODTs are perfect alternative for pediatric and geriatric patients with difficulty in swallowing , and uncooperative patients because of their convenience of self-administration and compactness. This communication reviews the appli?cations and technologies involved in formulation feature,lyophillization process,excipients selection,fast dissolving mechanism,and determination of disintegration time.

Drug safety evaluation in pediatric population:research advances / 国际药学研究杂志

The safety and risk assessment of pediatric pharmaceuticals has become a hot spot on drug development and man?agement in recent years. The shortage and unreasonable use of pediatric medicines and lack of preclinical juvenile safety evaluation of marketed pharmaceuticals have caused safety problems,a serious threat to the health and safety of pediatric population. Therefore,gov?ernments have formulated relevant regulative and administrative regulations and policies. In preclinical research ,due to the similarity of the young animals and children in the development process,a series of juvenile animal studies were carried out and the respective guidelines were gradually improved in Europe and the US. Therefore,the toxic effects of pharmaceuticals on children can be effective?ly predicted. In this paper,a detailed analysis and explanation is provided on the difficulties confronted with on R& D of pediatric pharmaceuticals,physiological differences between children and adults,and particularly,the importance and focus of preclinical safe?ty evaluation of pediatric pharmaceuticals,in order to offer a reference for the safety evaluation of pediatric drugs in China.

Analysis of Drug Use in Pediatric Patients from 78 Sample Hospitals in 7 Regions of China from 2013 to 2014 / 中国药房

OBJECTIVE:Analyze drug use of pediatrics in China,and to provide reference for promoting research,develop-ment and supply of pediatric drugs. METHODS:Analyze the data of drug use in 2 632 514 pediatric patients aged from 0 to 14 of 78 sample hospitals from Beijing,Shanghai,Tianjin,Hangzhou,Zhengzhou,Guangzhou and Chengdu in“The Hospital Prescriptions Cooperation Project”of Hospital Pharmacy Professional Committee of Chinese Pharmaceutical Association,statistical analysis was performed by using Excel and Access software. RESULTS:Pediatric patients in 78 sample hospitals of 7 regions had used 1 572 kinds of drugs from 2013 to 2014,but only 31.04%of drugs were pediatric drugs;both the ratio of pediatric drug types and the ra-tio of pediatric drugs use frequency had a great gap in different drug classifications. The ratio of drug use frequency in injection ad-ministration was 57.97%,and it was greatly higher than that of oral administration(31.04%). Among oral solid preparations,the ratio of drug use frequency for drugs with unreasonable specification was 29.57%,and ratio of drug types was 40.99%. CONCLU-SIONS:The pediatric patients had a great drug shortage in kinds,dosage forms and specifications in 78 sample hospitals of 7 re-gions during 2013-2014. Off-label drug use,high frequence of injection use,tablets used after breaking and other irrational phenom-ena were found in pediatric patients during clinical drug therapy,which reduced high risk of drug use. It is recommended that gov-ernment should strengthen and improve incentives mechanism of research,development and supply of pediatric drugs,so as to solve pediatric drug shortage in China,promote rational clinical drug therapy for children and guarantee the safety of drug use in pe-diatrics.