Generally, drug development requires appropriate studies in the target treatment population to evaluate their safety and efficacy. Pediatric medicines development follows the same principles and appropriate study data are needed to support information on the rational use of the drug in pediatric patients of the target age. However, the design and execution of clinical studies with pediatric subjects face more difficulties and challenges than adult studies, making it difficult or slow to conduct the trial, therefore, following the design and study methodology of traditional clinical trials,Significant impact on the clinical accessibility of pediatric medications and the availability of data sufficient to assess the rationality of the dose in children. This is one of the important reasons for the global shortage of children's drugs and off-label drug use. 

In order to seek better strategies and research methods for pediatric medicines development, drug regulatory agencies, pharmaceutical industry and academic circles in various countries are conducting in-depth exchanges and exploration, the starting point is very clear, that is to use more new methods and new technologies to obtain evidence of rational use of drugs in children,Save the resources of pediatric clinical research and reduce the risk of the trial. Using real-world methods to obtain reliable data and form evidence to support regulatory decision-making is one of many new methods and technologies that provide support for the development of new drugs for children, the expansion of pediatric indications, and the improvement of pediatric dosage.

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use,ICH) issued ICH E11 Supplement on 18 Aug 2017: Clinical Studies of Medical Products for the Pediatric Population(Clinical Investigation of Medicinal Products in the Pediatric Population E11 (R1)). This article introduces the application of real-world evidence in pediatric medicines development, especially long-term safety observations of drugs. On January 7, 2020, the National Medical Products Administration issued Guidelines for Real-World Evidence in Support of Drug Development and Review. It is clearly stated that the use of real-world evidence is a strategy for pediatric medicines development, such as to support expansion of the applicable population and dose modifications. 

In view of the above, considering the actual needs in pediatric medicines development and drug registration in China, timely transmission of drug regulatory authorities' consideration of new research concepts and methods, in conjunction with the implementation of ICH E11 (R1) guidelines in China,To help drug developers and clinical investigators to better understand the application of the Guidelines on Real-World Evidence in Support of Drug Development and Review in pediatric medicines development, this guideline is hereby formulated. 

This guideline highlights the concerns of real-world evidence in supporting drug development in children. For the basic concepts, basic principles and statistical methodology of real-world evidence, please refer to the Guidelines on Real-World Evidence in Support of Drug Development and Review. This guideline applies to all types of pediatric medications, including chemicals, traditional Chinese medicines and biological products.

This guideline represents only the current views and understanding of drug regulatory authorities, and is intended for the reference of drug developers and clinical investigators, and is not legally binding. With the progress of scientific research and the accumulation of practical experience, the content of this guideline will be continuously improved. For the application of this guideline, please refer to the ICH E11 (R1) guidelines, the Guidelines on Real-World Evidence Supporting Drug Development and Review, and other relevant technical guidelines at home and abroad. 

Pediatric medicines development should always be centered around providing evidence for clinical rational use of drugs in children. When the traditional Randomized Controlled Trial (RCT) is difficult to provide sufficient information, real-world evidence can be used as an adjunct to support the evidence of rational drug use in children.

Specific applications include, but are not limited to, the following:

(1) To provide evidence of safety;

At present, this is the most common mode of application of real-world evidence in pediatric medicines development. Due to strict eligibility criteria for RCTs, the trial population is poorly representative of the target population, and limited sample size and short follow-up time lead to insufficient detection of rare safety risks. For children, there are risks that cannot be demonstrated during the short-term phase of the trial and long-term safety observations are needed, such as the effects on developmental and changes in bone, reproductive system, behavior, and cognition. For drugs that have not been studied in pediatric clinical studies before marketing or have few data from pediatric clinical studies, there are also problems that the safety profile of drugs in children may be different from that of adults due to differences in growth and organ maturity, and safety observation of the actual drug population needs to be performed after marketing.

(2) supportive medication regimen optimization;

These include a wide range of categories, such as expanding or narrowing the applicable population (e.g., to younger children), optimizing the dose or frequency of administration (e.g. refining the dose according to kg body weight), refining or modifying the dosing procedure or process (e.g., equivalence with different types of juice, jam), etc. The purpose of this model is to refine the characteristics of the target treatment population based on the clinical needs of pediatrics, and to design and optimize the drug regimen based on the available therapeutical evidence. The results of the study were used to expand the clinical benefit population of the drug, improve the prescriptions of doctors and patient medication regimens, and support the update of drug label information.

(3) Evaluation of long-term clinical benefit

The use of surrogate endpoints (e.g., biomarkers) for response assessment in RCTs is permitted in some pivotal pediatric medicines registries, especially in disease areas where there is a clinically urgent need for use and where surrogate endpoints are relatively reliable. Such an approach is often accompanied or supplemented by long-term clinical benefit studies with clinical efficacy endpoints or endpoint events in the real treatment setting to improve the chain of evidence. In addition, the study of drug-related risk factors, drug combination, rescue drugs and methods can also be classified into this category. 

(4) To provide dose basis or verify the rationality of dose;

Such patterns are less commonly used in adult drug development but are not uncommon in pediatric medicines development. Due to the long-term and extensive off-label use of drugs in pediatric patients, a great deal of real-world data have been accumulated, but the dose for children at different age stages is determined based on the conversion of body weight differences between adults and children and the physician's experience reported in the literature, and there is no reliable research evidence to support its labeling,It is also difficult to verify the rationality of the dose through new prospective randomized controlled clinical studies, so the dose rationale for children can be supported by real-world evidence, including retrospective medical data analysis and prospective prescription data collection. In addition, the reliability of Pediatric dose and safety Extrapolation can be derived from available adult data when a Pediatric Extrapolation method is used to obtain a Pediatric dosing regimen.Post-marketing real-world evidence was used to further justify dosing in pediatric patients.

(5) Other

Considering the acceptability of pediatric population, the observational dimensions and test indicators of pediatric medicines development programs usually only meet the minimum criteria for evaluation needs, and indicators that are not strongly related to the main study objectives are often not recommended to be included in the trial design, such as the indicators of health economics of drugs, quality of life, etc. However, such information is important for understanding the overall situation of pediatric medication or guiding public health services for children. Relevant research information can be obtained from real-world evidence. 

Real-world evidence is not a simple collection of data, but rather reliable quality data in a real medical setting that answers specific drug-related questions. Therefore, the timing of the application of real-world evidence is determined by specific issues. At present, the application of real-world evidence in pediatric medicines development often occurs in the following situations:

(1) Long-term medication risk monitoring, such as the effects of drugs on children's growth and development;

(2) To meet the diversified needs of children with concomitant medication, concomitant food and other studies;

(3) A large amount of data has been accumulated in clinical practice, which is expected to provide sufficient evidence for specific problems, such as safety and efficacy data of off-label dosage, concomitant medication data, etc.;

(4) The pediatric dose determined by the extrapolation model can be used as validation evidence for approval or conditional approval in the case of high extrapolation reliability and low safety risk;

(5) It is difficult to independently carry out RCT in a certain age group or a certain age group of population cannot participate in key RCT, such as premature infants, neonates, etc.

Real-world research is a research method that complements and supports traditional clinical trials. The difference between real-world research and traditional clinical trials is only due to the different environment in which the data are generated. Since the data generated from real-world studies will be used to support regulatory decisions, there are stringent requirements for their study design, data quality, statistical analysis methods, etc. 

In pediatric medicines development, it is usually reasonable and feasible to conduct real-world studies or traditional clinical trials. The final choice of which or both depends on the in-depth understanding and overall grasp of specific disease characteristics, target treatment population characteristics, drug properties, test conditions, etc. The basic principle should be to ensure that the requirements of drug safety and efficacy evaluation are met, and the research resources for children should be saved as much as possible, and data quality and research efficiency should be taken into account.

(1) Real-world evidence to support post-marketing safety evidence collection

Fluticasone propionate inhalation aerosol is an inhaled glucocorticoid developed by GlaxoSmithKline and has been imported into China for more than ten years for asthma in children and adults. The product applies for the expansion of the applicable population in China from the approved "Children ≥ 4 years of Age" in China to "Children ≥ 1 Years of Age" consistent with the overseas approval using clinical study evidence for children ≥ 1 year of age. With reference to the Technical Guidelines for Extrapolation of Adult Drug Data in Pediatric Clinical Trials and Related Information, it is recommended that the pharmacological mechanism of this product is clear, has reliable evidence of overseas pediatric clinical studies and domestic pediatric clinical application basis, and the clinical efficacy for pediatric population is clear,After benefit-risk assessment, a clinical study exemption for Chinese children was implemented and an extension of the applicable population in China to children ≥ 1 year of age was approved. At the same time, the approval document calls for a post-marketing safety study in Chinese children with asthma aged 1-4 years, i.e., to further enrich the safety evidence for expanded use in lower age groups in China without concerns about efficacy and overall safety.

The product completed a real-world observational study to monitor the safety of medications in children aged 1-4 years in accordance with the requirements of the approval document, and clinical medication data were collected and included in the analysis at designated medical units. Strictly follow the drug dosage and method of administration recommended in the package insert for children aged 1-4 years. In addition to designing general safety observation indicators, the key safety observation indicators were designed according to the medication risk information in the product labeling. The results of the study were used to enrich the evidence of safety and to assess the need to adjust the current labeling information.

(2) Real-world evidence supports the rationality of extrapolated dose;

Ibuprofen injection is a non-steroidal antipyretic and analgesic drug. The dosage form is injection, which is administered by intravenous drip. This product is first approved for use in Chinese adults, and after a period of time on the market, the approved pediatric indication of the original drug is requested to be added by exempting clinical studies in Chinese children. With reference to the recommendations of the Technical Guidelines for the Extrapolation of Adult Drug Data in the Use of Drug Clinical Trials and Related Information in the Pediatric Population, the product provides more complete data evidence, and finally obtained the approval of the pediatric indication through the implementation of the pre-marketing clinical study exemption.

This product is a generic drug, and the pediatric clinical study completed with the original drug is used as the data basis, and the pediatric extrapolation modeling simulation is used to infer the dose for children in China. Although the data source is clear, the quality is reliable, and the analytical science provides the evidence to support the pediatric medicines regimen in our country, considering the lack of data on the direct participation of Chinese children in the study, it is still necessary to carry out the verification of the rationality of Chinese children's dose after marketing. According to consulting pediatric clinical experts, the main population of intravenous antipyretic analgesics in clinical practice in China is young children with acute illness, i.e., those who are in urgent condition and unable to cooperate with oral administration. This population is not only the main beneficiary population of this variety, but also the population with the highest risk of drug use. Therefore, the approval letter for this product requires a post-marketing real-world study of young children to complete the rationality of the dose in the most beneficial and risky age group (young children). The results of the study were used to consolidate extrapolated conclusions and to assess the need to adjust the current labeling information. 

As a form of clinical studies, research projects for the purpose of obtaining real-world data should also follow the general principles of clinical studies, as well as special considerations for pediatric clinical studies, in accordance with ICH E11 (R1) guidelines and relevant technical requirements published in China.

When using real-world data in pediatric medicines research and development, special attention should be paid to the source and quality of data, and the real-world data should be converted into real-world evidence through rational design and scientific statistical analysis methods, so as to provide reliable basis for supporting the information of rational drug use in children.

Compared with the adult population, basic and clinical studies targeting children are relatively limited and may result in insufficient knowledge or information or deficiencies in certain key areas. Special attention should be paid to the mastery of developmental physiology, pathophysiology, pharmacology, and therapeutics in the application of real-world evidence.

The application of real-world evidence in pediatric medicines development faces feasibility problems, including whether pediatric clinical information resources and network construction can meet the requirements of data collection and analysis, and whether the research unit has the conditions for information collection. Such issues may have an impact on the quality of evidence and should be considered in pediatric medicines development programs.

The use of real-world evidence to support pediatric medicines development is at a stage of progressive construction and improvement, and drug developers and clinical investigators are encouraged to maintain good communication with drug regulatory authorities on the application of real-world evidence in pediatric medicines development in order to build a broader consensus.