Current Situation of Clinical Trials of Drugs for Children's Indications in China

Background: The number of pediatric outpatient visits in the general hospitals of China shows an increasing trend year by year. To analyze the current situation of clinical trials of drugs with indications for children in China in order to provide references for research and development of drugs for children and in formulating relevant policies. Methods: Drug clinical trials with indications for children registered before January 9, 2020 were retrieved based on the drug clinical trial registration and information publicity platform. The data were extracted and statistically analyzed by excel 2010 and SPSS 22.0, respectively. Results: There were 256 clinical trials of drugs with indications for children, which accounted for 2.61% of the total registered trials. The overall average annual growth rate of the number of trials from 2007 to 2019 was 43.30% (P=0.0000). The host company and the lead organization were mainly located in the eastern and northern parts of China. There were 67 trials (26.17%) with children as subjects; 102 trials (39.84%) with research drugs only for children; the drug type was mainly the chemical drug, and indications mainly included infections, nervous and mental diseases and respiratory diseases. Conclusion: The prospects associated with pediatric drug development are positive, but it still needs new incentives or technical guidance to further promote.

drug use in children by encouraging research and development, speeding up the application and evaluation, and improving the system construction. The National Health Committee and other departments have issued three batches of pediatric drug lists for research and development by the end of 2019 [9]. With the encouraging measures, the number of clinical trial institutions quali ed for conducting pediatric clinical trials in China has been signi cantly increased in recent years [8]. Thus, in this study, clinical trials of drugs with indications in children were analyzed in China to provide reference for research and development of pediatric drugs and formulation of relevant policies.

Data source
To strengthen the supervision and management of clinical trials of drugs, promote the openness and transparency of clinical trial information of drugs, protect the rights, interests and safety of subjects, the Medical Products Administration (NMPA) in China has established a web-based database for clinical trials. This is named as the Drug Trial Registration and Information Publication Platform, and was o cially released in 2013. It is a national authoritative database of clinical trials in China, and all drug clinical trials being done including phase I to IV trials should be registered and the bioequivalence studies must be registered on the platform before enrolling the rst patient. The NMPA then routinely crosschecks the information on the platform with the related data and summary report submitted with a given trial to ensure that the information is accurate and up to date. Retrospective registration is required for trials that started before 2013, but is not completed for the related new drug applications.
Information about the registered drug clinical trial includes sponsor's information, such as the applicant name, contact information, etc.; trial's information, such as the name of the drug studying, indications, drug types, study purposes, trial design, subject information, inclusion and exclusion criteria; researcher's information, ethics committee approval information, trial status, etc. After retrieval, there are 9797 drug clinical trials registered on the platform as of January 9, 2020.

Trials Screening And Data Extraction
Trials with indications of "er" in pediatric patients in Chinese or "adolescent" were retrieved for inclusion.
Two authors have respectively screened the retrieved trials, and excluded the repeated registration trials, trials that have been suspended, non-drug trials, and trials without indications for children. Two authors have reviewed the full information of all the included trials and extracted the study characteristics, and any disagreements were resolved through discussion or by consulting a third author. The following information of the trials, including registration number, trial status, trial phase, date of rst ethical approval, name of the sponsor and province of the sponsor located, the rst a liation and province of the principal investigator located, number of research centers, name, type, dosage form and indications of the drug studied, age of the subjects, children's age speci ed in the indication, whether a data monitoring committee (DMC) have been established, and whether insurance had been purchased for participants, were recorded. We de ned the rst ethical approval date of the trials as the date of the trials to make annual trial number statistics. The provinces of the sponsor and the principal investigator were divided into seven regions according to the China's seven geographical divisions, the north, east, south, central, northeast, northwest and the southwest. For foreign sponsors, their registered province was recorded in China. For drugs with indications for adults and children, only the indications for only children were recorded. In this study, the indications of studied drugs were coded according to the International Statistic Classi cation of Diseases and Related Health Problems, Tenth Revision, International Classi cation of Diseases (ICD)-10 classi cation.

Statistical analysis
Descriptive analyses were used to summarize the data, frequency (percentage) was used for qualitative data, and median (range) was used for quantitative data. A simple regression model was used to analyze the trends in the number of trials included, with P < 0.05 representing a statistically signi cant difference, and the year of the trial was de ned by the date of the rst ethical approval. All statistical analyses were performed on a personal computer with the statistical package SPSS for Windows (version 22.0).

Results
A total of 347 clinical trials with indications including "er" of infant and child were retrieved in Chinese or "adolescent" were screened for inclusion. Of these, 77 trials were excluded due to duplications and repeated registrations, and 11 trials have been suspended, 2 non-drug trials, and one trial with indications not for children were excluded. Finally, there were 256 trials included for data extraction and analysis, accounting for 2.61% of the total registered number as of January 9, 2020.

General characteristics of the trials with indications for children in China
The general characteristics of trials with indications for children in China were shown in Table 1. Considering the 75 multiple-center trials, the number of centers was 8(3 ~ 377), and the trial with 377 centers was an international multiple-center phase clinical trial. In addition, 11 of the 16 trials for which a data safety monitoring committee have been established were multiple-center clinical trials. Of the 256 trials, the initial registration date of the trial was from July 2, 2013 to January 7, 2020, and the rst ethical approval date of the trials was from September 19, 2007 to December 26, 2019. By considering the rst ethical approval date, the number and the phase of trials distributed in different years was shown in Fig. 1. A total of 67 trials (including 4 phase , 20 phase , 26 phase , and 11 phase trials) were conducted among children age ranging from 0 to 18 years. Ten trials included both adults and children as subjects, and 179 trials (including all 160 bioequivalence trials) included only adults as subjects. A simple regression model revealed that the overall average annual growth rate of the number of trials was 43.30% (P = 0.0000). As shown in Fig. 1, the number of trials included had been signi cantly increased since 2017. In addition, a simple regression model based on the number of phases I to IV trials showed an average annual growth rate of 22.12% (P = 0.001).

Geographical location of the trials with indications for children in China
The geographical distribution of the sponsors of the 256 trials was shown in Fig. 2. More than 40% of the sponsors were located in the eastern China. The geographical distribution of the principal investigator involved in the 256 trials was shown in Fig. 3, and the trial institutions were mainly distributed in the east, the north and the central China, with Beijing, Jiangsu and Shanghai as the major ones.

Distribution Of The Studied Drugs And Its Dosage Form
The types of research drugs involved in the 256 trials and the distribution of the main dosage forms were shown in Fig. 4 Fig. 4 included syrup, powder, oral solution membrane and needle-free percutaneous injection administration system, respectively. All traditional Chinese medicine/natural drugs were special drugs for children, and their dosage forms mainly included granules and patches. Of the 40 kinds (15.63%) of biological products, 33 were speci c drugs for children, mainly in the form of injections.

Distribution Of The Indications Of The Research Drugs
According to ICD-10, the organ system of diseases related to the indications was shown in Fig. 5. Among them, 92 drugs (35.94%) were indicated for infections, followed by neurological, psychiatric and respiratory diseases. Of the 92 clinical trials with indications to infection, 26 were digestive system infections and 22 were respiratory system infections.

Discussion
The Drug Trial Registration and Information Publication Platform was started to operate in November 2012 but was not o cially applied until 2013, and the clinical trials included in this study did not completely incorporate the clinical trials that obtained approval documents before 2012. Besides, the purpose of this study was to analyze the clinical trials of drugs with indications for children, and re ect the research and development situation of drugs for children in China, so we included studies with indications for children but apparently some of the studies were carried out in adults, although the drugs were indicated for children.
According to the retrieval results, there were still very few drugs (2.61%) for pediatric indications in the clinical trials of registered drugs that are currently carried out in China, and only 67 trials (26.17%) with children as subjects, only 102 trials (39.84%) with research drugs only for children. As a special and vulnerable group, recruitment and ethical issues make the conduction of clinical trials in children more challenging. How to further improve or innovate the technical methods of clinical trials, improve the use of e cient databases such as electronic medical record system, and strengthen the cooperation among industries, administrative departments, medical institutions, research doctors and subjects, to further promote the development of clinical trials of pediatric drugs and the application of data, has long been a problem of discussion [10]. On January 3, 2020, the State Drug Administration has issued the Notice of State Drug Administration on Guiding Principles for Issuing Real World Evidence to Support Drug R&D and Evaluation (Trial) (No.1, 2020) [11]. This pointed out that in areas of drug use for children, the use of real-world evidence is warranted to support the expansion of indications as this is also one of the situations where drug regulatory decisions may be applicable. This provides a new direction for research and development of drug use in children based on real-world evidence.
For a long time, the research and development of drugs and their preparations have mainly focused on adults and their associated diseases, and further development of drugs suitable for children of different ages has faced a great challenge [12]. In this study, the dosage forms of chemical drugs were still mainly tablets and capsules, which are commonly used by adults. Studies have shown that even small infants can take small doses of solid dosage forms, such as micro tablets [13]. In addition, other oral mucosal absorption dosage forms, such as orally disintegrating lms, are also expected to become new dosage forms suitable for children [12]. Among the clinical trials included in this study, only montelukast sodium has the dosage form of orally soluble lm. In terms of age for indications, of the 256 trials included in this study, 3 drugs were used for premature infants and newborns, and 11 drugs were used for infants only. Studies have shown that the incidence rate of off-label use of drugs in newborns was about 90% [14], and clinical trials in young children are facing greater ethical challenges, especially the sick newborns and premature infants, and might require new incentives or relevant policies to select the drugs that are mostly needed for research in trial design and development [15].
A great progress has been made in the study of drug use for children worldwide in recent years. Studies have shown that in the past 15 years, a total of 1,200 pediatric studies have been submitted to the U.S. Food and Drug Administration. More than 700 drug speci cations have been revised and information on pediatric use has been provided. In addition, the failure rate of pediatric clinical trials has been decreased from more than 40% to about 20% [16]. In terms of quantity, the clinical trials of drugs with indications for children in China are increasing year by year, but excluded the bioequivalence trials, and the phases to osclinical trials were still less than 20 every year. In addition, there are still large regional differences between the sponsors and research institutions, with obvious advantages in the east and the north. Geographical distribution of trial sponsors Note: The designations employed and the presentation of the material on this map do not imply the expression of any opinion whatsoever on the part of Research Square concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. This map has been provided by the authors.

Figure 3
Page 12/13 Geographical distribution of principal investigators Note: The designations employed and the presentation of the material on this map do not imply the expression of any opinion whatsoever on the part of Research Square concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. This map has been provided by the authors.

Figure 4
Drug types and main dosage forms of research drugs (n=256) Figure 5 Distribution of indications of research drugs (n=256)