Specifics of conducting pediatric clinical trials with children in Russia

There is a clear lack of pediatric medications on the modern pharmaceutical market: there are no special pediatric medications for 75% of pediatric diseases, more than 70% of medications pre-scribed to children have not been studied in the pediatric population in clinical trials, and 90% of medications prescribed to newborns have not been tested in this age group. In this article, we would like to talk about the peculiarities of conducting clinical trials with children because children are not little adults, and treating children requires a special approach.

Before the introduction of requirements for conducting clinical trials with minors, it was normal prac-tice to use in the treatment of children medicines intended for adults. At the physician’s discretion, the dose was adjusted and the form of the medicine could be changed (for example, the tablet was crushed and mixed with a sweet liquid) to make it more comfortable for the child to take. However, there was a lack of studies that did not take into account the age specifics of patients related to the pharmacokinetic and pharmacodynamic parameters of the drug. The lack of data on the use of the drug in different age groups led to the fact that minor patients ended up receiving drugs with unstudied safety, bioavailability, and efficacy. Therefore, there has been an urgent global question: should we prescribe medications tested only on adults or conduct clinical trials with minors? Below we pre-sent current approaches to solving this problem.

According to data given in the ACTO’s final bulletin for 2019, in 2019, 66 approvals were issued for IMCTs involving minors (21% of all MCTs), of which 47 were for IMCTs involving only the pediatric population. At the same time, in approximately a quarter of the trials cited above, the lower age limit for participants in clinical trials was cut by the Ministry of Health from 1-6 years old to at least 12 years old. This is not just due to the Russian Ministry of Health’s desire to ensure patient safety, but also to the specifics of Russian legislation regarding the conduct of clinical trials with the participation of minors. In the USA and Europe clinical trials involving minors are regulated by the Pediatric Research Equity Act and the Pediatric Regulation No. 1901/2006 and Amendment 1902/2006, which clearly describe the procedure for clinical trials and registration of medications involving mi-nors. Until April 2010, clinical trials involving minors in the Russian Federation were regulated by only one subparagraph of the law “On Medicinal Products” No. 86-FZ of 22.06.1998: “Clinical trials of medicines on minors are not allowed, except in cases where the medicinal product under study is intended exclusively to treat childhood illnesses or where the purpose of the clinical trial is to obtain data on the best dosage of the medicinal product for the treatment of minors. In the latter case, clinical studies of the drug on minors must be preceded by clinical studies of it on adults.” In the current-ly enacted law “On Circulation of Medicines” from 12.04.2010 N 61-FZ in article 43, subparagraph 5 we see: “conducting a clinical trial of a medicinal product for medical use with the participation of children as patients is allowed only with the written consent of their parents or adoptive parents. Children may be considered as potential patients in such a study only if its conduct is necessary to promote children’s health or prevent infectious diseases in children, or if the purpose of such a study is to obtain data on the best dosage of a medicinal product for the treatment of children. In these cases, such research must be preceded by a clinical trial of a medicinal product for medical use in adult citizens, except if the medicinal product for medical use understudy is intended exclusively for use by underage citizens,” which already gives “more discretion,” but without departing from the requirements of the GCP.

However, in the conduct of clinical trials involving minors, Sponsors, the СROs, Ethics Committees, and physician-researchers often not only follow the local law but are also guided by current trends. For example, one of these trends is the availability of informed consent not only for the parent but also for the child, where basic information about the clinical trial is presented in an accessible form (age-appropriate, sometimes with pictures). This makes it possible to document that information about the potential benefits of the medicine, possible side effects, and trial procedures are presented to the direct participation of the trial in a form that is understandable to him.

Therefore it is possible to highlight the following features of developing and conducting clinical trials of medications with the participation of minors:

• Creation of a drug-taking into account the age-specific pharmacokinetics of the target group of pa-tients;
• Creation of a convenient dosage form for use by children (syrup, suspension, chewable tablets, small tablets) – at the stage of drug development;
• Particular attention to drug safety – even without efficacy studies in adults, if possible, the safety of the drug must be proven in adults;
• The motivation of parents of potential study participants – parents of young patients must be confi-dent that their child will receive a safe drug under the close supervision of investigational;
• Creation of understandable and tested on children questionnaires used in the study;
• Special attention to children’s rights;
• Creation of maximum comfort for study participants – providing cabs, meals, and, if possible, home visits to patients.

Developing a clinical trial program for drugs for minors is a multifaceted and time-consuming pro-cess that requires coordinated teamwork between the Sponsor, the CRO, and the trial sites -from the earliest stages of drug development to the further monitoring of drug safety and effectiveness to the drug’s market launch.