CDE publicly solicits the opinions of the Guidelines for Clinical Pharmacological Research in Paediatric Drug Use (Draft for Comments).

Introduction: In order to meet the needs of drug research and development and registration in children in China, encourage the use of new technologies and methods to carry out clinical trials of children's drug use, and further clarify the clinical pharmacological requirements of pediatric drug use.
. In order to meet the needs of research and development and registration of pediatric drugs in China, encourage the use of new technologies and methods to carry out clinical trials of children's drug use, and further clarify the technical requirements of pediatric drug clinical pharmacology, our center has drafted the Guidelines for Clinical Pharmacology Research in Paediatric Drug Use (Draft for Comments), and is now open for comments.
welcome from all walks of life to put forward valuable comments and suggestions, and please give us timely feedback.
for comments shall be one month from the date of publication.
please send your feedback to the following contacts: Contact: Han Hongying Contact: hanhc@cde.org.cn Thank you for your participation and support.
The Drug Review Center of the State Drug Administration drafted the Guidelines for Clinical Pharmacology Research in Paediatric Drug Administration (Draft for Comments) on September 1, 2020, which states that in order to meet the needs of drug research and development and registration in China, new technologies and methods are encouraged to conduct clinical trials of children's drug use, and further clarify the technical requirements of clinical pharmacology for pediatric drug use, the Drug Review Center has organized the Draft guidelines for clinical pharmacology for pediatric drug use (draft for comments) to form a draft for comments.
the relevant information will now be explained as follows: First, the purpose and background of the drug description of paediatric test data and usage information is insufficient, is a common problem in the international paediatric drug use.
it is challenging to meet the reasonable basis for the use of children's medication instructions while avoiding unnecessary clinical trials.
with the development of clinical pharmacology technology, the use of new methods, new technologies can help solve the difficulties faced in clinical trials in children.
can make full use of existing knowledge, optimize the development of pediatric drugs, get a reasonable dose of pediatric drugs, while avoiding unnecessary clinical trials.
guidelines for better guiding companies to develop medicines for pediatric populations.
II. The main contents and explanations Of the differences between children's physiological development and adults, these guidelines expound the special considerations of pediatric drug clinical pharmacology, clarify the clinical pharmacological research to be carried out in the process of pediatric drug research and development, the practical difficulties and solutions, the application of model simulation methods in the research and development process, and provide ideas for the research and development of pediatric drugs.
Guidelines for Clinical Pharmacology in Paediatric Pharmacology (Draft for Comments) 1 Outline that pediatric population clinical pharmacology is an important branch of clinical pharmacology.
Its research object is children, is a group of growth and development in dynamic changes, its anatomy, physiological structure and organ function and adults are very different, different age stages have different anatomical and physiological characteristics (neonatal, infant, childhood, adnatal).
Because of the particularity of children's clinical research, such as ethical considerations, practical difficulties, it is more difficult to carry out clinical trials in accordance with the general steps of adult drug research and development, often need to adopt quantitative pharmacological methods, integrated use of existing clinical research information (such as pediatric population physiological characteristics, adult clinical research data, etc.), to provide a basis for clinical trials in pediatric population, to avoid unnecessary clinical research.
Clinical pharmacology studies in pediatric populations usually collect data on pharmacodynamics (PK), pharmacological dynamics (PD) and dose effect relationships in pediatric populations of different ages to support optimal dose determination and safety and effective evaluation.
provides the basis for clinical use of doses in pediatric populations.
guidelines apply to the development of chemicals and biological products.
chinese medicine can be carried out by reference.
guiding principles only represent the current views and understandings of drug regulatory authorities, for the reference of research and development enterprises, not mandatory legally binding, as scientific research progress, the relevant content of these guidelines will be constantly improved and updated.
2 Clinical pharmacology generally considers that clinical pharmacological studies are not usually aimed at direct benefit from the treatment of the subject's disease, and in view of ethical requirements, paediatric clinical pharmacology studies should not be conducted in healthy children and should be conducted in specific patients with adhesive disorders.
clinical pharmacology research should determine the age and age stratage of subjects conducting clinical trials according to drug characteristics and pediatric physiology and pharmacological characteristics.
To the extent possible, data on pharmacogenetics, pharmacological dynamics, and exposure-effect relationships should be obtained, and information on drug metabolism enzymes, excretion characteristics, and transporter at different ages should be collected to provide a sufficient basis for decision-making in research and development strategies.
in the implementation of research, should generally be in accordance with adults, adolescents, children, infants and young children and other age groups gradually carried out.
2.1 Changes in the growth and development of pharmacodynamics in pediatric populations can lead to substantial changes in pharmacodynamics, which are usually required to be studied in different age groups of pediatricians to evaluate their pharmacogenic characteristics, and to link the pharmacodynamic characteristics of research drugs with parameters that characterize the developmental stage of pediatric populations (e.g. height, weight, or body surface area (BSA), etc.).
and development of pediatric population affect drug absorption, distribution, metabolism and excretion process, leading to differences in drug exposure in pediatric population.
proportion of metabolites produced in the body and the main metabolic pathways may vary from paediatric population to adult population, as well as to different age groups in pediatric population.
removal rate is usually an important parameter to determine the dose of medicine at different ages in pediatric population, and is an important part of clinical pharmacology research in pediatric population.
is the main reason why pharmacodynamics studies are usually needed in pediatricians of different ages.
to carry out standard pharmacodynamics research in pediatric population, usually require intensive sampling, blood harvest, may encounter difficulties, such as compliance.
Compared with the standard pharmacodynamic analysis, group pharmacodynamics can analyze the sampling data that are not rich (i.e. sparse), so as to optimize the blood collection scheme and reduce the amount of blood collected, so it is often used in the study of pharmacodynamics in pediatric populations.
If there is no adult PK data base, or if the study is conducted only in the pediatric population, intensive blood collection PK studies should be conducted in pediatric patients, including but not limited to single-dose and multi-dose administration studies.
should be determined on the basis of existing knowledge to avoid unnecessary exploration tests.
the relevant contents of pharmacodynamics can refer to the "Technical Guidelines for the Study of Pharmacological Dynamics in Paediatric Populations".
2.2 Pharmacological dynamics should obtain and analyze the pharmacodynamic characteristics, pharmacological dynamics characteristics and exposure-effect relationship of pediatric population on the basis of adult research results.
PD studies include the relationship between drugs and effectiveness and safe biomarkers, and/or clinical endpoints.
in pharmacological dynamics studies, if clinical endpoints cannot be directly determined due to effect delays, etc., appropriate biomarkers can be selected instead of clinical efficacy or safety endpoints.
biomarkers should usually be evaluated first in the adult population, and their applicability to the pediatric population will depend on the degree to which the pathophysiological and pharmacological responses of pediatric diseases are similar to those of adults.
3 Paediatric preparations Pediatric preparations are the focus of pediatric clinical pharmacology research, aimed at providing pediatric patients with accurate drug treatment programs and improve compliance.
if the drug has paediatric adaptation, it is suitable for the age stage of the pediatric patient.
Applicants may also develop pharmaceutical formulation formulations applicable to pediatric patients, but the following information should be provided in the study: (1) how to accurately quantify to the target concentration using commercially available devices; treatment needs, (3) all accessories, including diluents, suspensions, orthotics and colorants, etc., (4) information about drug containers and storage requirements, and (5) stability studies of preparations should be provided.
can be carried out in adult subjects of paediatric preparations and adult preparations of the relative biological utilization of the study.
should be concerned about the potential impact of food or shape agents on bio-utilization.
4 Paediatric Research Method 4.1 All available information and data, including differences in organ function and effects on pharmacological characteristics of people of different ages, disease knowledge, epidemiological conditions, non-clinical trial data, PK, PD, clinical effectiveness and safety differences between adults and pediatric populations, are required before PK research design clinical trials are conducted only.
When the following conditions are met: (1) the disease progression and treatment response of the target adaptation are similar between adults and pediatric populations;
can be calculated or modeled based on the information collected, and it is assumed that the expected dose similar to that of adult exposure can be achieved.
PK study to determine that exposure obtained at doses used in pediatric populations was similar to adult exposure, it was possible to use adult PK-PD data, briddle dose and effectiveness data.
is commonly used in the field of antimicrobial therapy.
4.2 PK/PD study When the disease progression and treatment response of target adaptive disorders are similar between adults and pediatric populations, but the in vivo exposure effect relationship of the drug is not fully defined between adults and pediatric populations, or is not considered to be completely similar, PK/PD studies should be conducted to compare the similarity of exposure-effect relationships in adult and pediatric populations and to determine the dose of pediatrics based on the exposure-effect relationship seen in pediatric patients.
Before carrying out the PK/PD study in pediatric population, there should be a clear relationship between adult exposure effect, and on the basis of adult research results, PK/PD study in pediatric population should be carried out to analyze the difference or similarity between the exposure effect of pediatric population and adults.
PD indicators can be clinically detected or biomarkers.
selected PD indicators are validated by adult studies.
method is commonly used in the field of anti-arrhythmic therapy.
4.3 PK/PD cannot bridge if a comprehensive analysis of the information and data available to support the disease processes and treatment responses of target adaptation and the in vivo exposure effects of the drug are not similar or difficult to determine between adults and pediatric populations, then a comprehensive and systematic clinical trial of paediatric population drugs is required.
PK study is not required at all ages, but where available data fully demonstrate the reasonableness of the dose.
can be used in the Technical Guidelines for Extratrodes from Adult Drug Data to Paediatric Populations.
5 The design of the pediatric research plan and the key point 5.1 The optimal dose for the pediatric population using the determination of the dose is a core issue in the clinical pharmacological research of the pediatric population, and since the safety information of the experimental drug in pediatrics, especially in newborns or infants, is very limited, the dose of administration used in the initial study of pharmacodynamics needs to be carefully considered, and the PBPK model can be used to help determine the best administration plan for each age group.
Factors considered in general include: (1) the relative bio-utilization of drugs compared to the original preparation (adult preparations) of new preparations (for pediatric populations); (3) biological activity and toxicity of the drug, (4) pharmacological data for adults or other pediatric populations, (5) changes in drug absorption that may be caused by the drug dosage form in pediatrics, and (6) reference information for PK/PD data in pediatric populations with similar mechanisms of action.
if a separate pediatric effectiveness study is not conducted (i.e., adult data are completely extratroted), the PK study of the pediatric population should determine how to adjust the dosing regimen to reach adult body exposure levels.
differences in PK measurements and/or parameters between age groups or between children and adult patients should be explained by their effects on dosage, safety and/or efficacy.
the applicant should propose a determination of whether the relationship of exposure effects is similar.
dose is usually standardized weight (mg/kg) or BSA (mg/m2).
quantitative pharmacology models (PK-PD, E-R models, etc.) are commonly used in determining optimal doses in pediatric populations.
the research purpose, we should choose the appropriate model, pay attention to the premise of the model hypothesis, and verify the model in order to get reliable results.
, for example, to develop a physiologically based pharmacodynamic model (PBPK), the PBPK model should be modeled using clinical data obtained from adults before it is extratrodomed to the pediatric population.
the PBPK model method can be used to predict the level of exposure in subsequent groups before the pharmacodynamics study advances to the next group at a lower age.
challenge of using the PBPK model method to predict the pharmacological characteristics of children is to identify the key physiological or pharmaceutical factors that cause PK differences in children and adults, and to describe such differences with reasonable mathematical equations.
Using the PBPK model to extratroge the pharmacokinetic characteristics of children from adults should be noted whether the following assumptions establish the acronym BA: Bioavailability, Bioequaivence, Bioequaivence BSA: Body surface area, body surface area E-R:Exposure-Response, exposure-effect PBPK: Physically based on pharmacokinetics, physiologically based pharmacokinetic model PD: Pharmacodynamics, Pharmacological Dynamics PK: Pharmacokinetics, Pharmacokinetics References, Technical Guidelines for Pharmacokinetics Research in Pediatric Populations, Technical Guidelines for The Extratroctic Data of CFDA-CDE, Technical Guidelines for The Extratrocence of Adult Drug Use Data to Pediatric Populations, CFDA-CDE, Technical Guidelines for Clinical Trials of Medicines in Pediatric Populations, CFDA-CDE4. Clinical Investigation of Medicinal Products in the Pediatric Population, ICH E11, released in July 2000