Children have unique physiological and psychological characteristics, so conducting pediatric drug clinical trials often presents numerous challenges. This study comprehensively analyzed the data of completed and discontinued trials conducted in mainland China. The results revealed an annual increase in trials initiated, but imbalances persist in various aspects such as drug types, ages, sponsors and trial institutions, and disease. We performed subgroup analyses on the duration of completed pediatric drug clinical trials and explored the factors and reasons influencing the trial discontinuation.
From 2003 to 2023, over two decades, the number of concluded pediatric drug clinical trials in Mainland China has been increasing annually, with an average annual growth rate of 19.7%. This fully reflects the rapid development of trials in China, a trend that is closely linked to the government’s high level of attention and continuous promotion in recent years [4, 5, 24, 25]. However, the data also reveal imbalances in various aspects, such as drug types, diseases, and age. These imbalances not only lead to excessive competition and resource waste in some areas but also result in insufficient attention and support for critical areas such as rare diseases and neonatal drugs, which further exacerbates the serious challenges in the safety and accessibility of some pediatric medications [6, 26, 27].
In response to this issue, China has taken a series of effective measures. In addition to issuing a series of technical guidelines and policies to encourage research and development, China has also introduced innovative approaches for rare diseases and neonatal drugs such as patient-centred and data extrapolation [28, 29]. Moreover, urgent rare disease drugs have been exempted from clinical trials to accelerate market access, aiming for breakthroughs in these critical areas [30]. Notably, in the past two years, China has introduced the “Care Program” (Patient-Centered Action for Rare diseases Encouragement) and “SPARK Program” (Support Anti-tumor drug R&D for Kids) targeting rare disease therapeutics and pediatric oncology pharmaceuticals. These initiatives aim to enhance medication accessibility and safeguard treatment needs for affected patient populations [31, 32].
Furthermore, national and regional medical centers have been established to equitably distribute pediatric medical resources. Meanwhile, the establishment of the “Chinese Pediatric Clinical Trial Collaboration Network” and the “Chinese Pediatric Drug R&D and Industrialization Alliance” aims to enhance the level of pediatric drug clinical trials and boost research and development capabilities. However, China’s current policies predominantly focus on encouragement and guidance, yet they are devoid of both mandatory legal requirements and economic incentives, such as the “pediatric exclusivity (PE)” observed in Europe and America, as well as the premium policy akin to Japan’s “price addition for pediatric drugs” [24, 33]. This absence poses challenges to the advancement and innovation of pediatric drugs and the balanced development of clinical trials. Therefore, it is imperative to draw on advanced foreign drug regulatory experiences, formulate laws, and establish a regulatory system that combines economic incentives with mandatory requirements to achieve a win-win situation for both society and industry [4, 34].
Clinical trials are the most expensive and time-consuming phase in drug research, hence saving time can reduce costs and bring higher economic benefits to sponsors. The study results show a reduction in the duration of trials in China, which may be related to the increase in domestically conducted pediatric trials that are less time-consuming, along with the continuous improvement in the level of pediatric clinical research and the trial design ability in China [35, 36]. In the subgroup analysis of trial phases, we discovered that trials with seamless design had shorter durations. This is because seamless design efficiently integrates resources across trial phases, minimizing repetitive work and time waste, thus enhancing trial efficiency [22, 23]. Additionally, oncology pediatric trials take longer, while vaccine pediatric trials take shorter durations, mainly due to the complexity and treatment difficulty of different diseases. Researchers can develop more scientifically rigorous and contextually appropriate clinical trial protocols that align with the specific characteristics of various diseases, thereby optimizing trial durations. At the same time, we also found that pediatric trials using blinding, not including adults, involving biological products, and conducted by domestic sponsors tend to have relatively shorter trial durations. These factors may have a positive impact on reducing trial durations. For example, blinding can mitigate bias and interference, thereby enhancing data quality and improving trial efficiency. Trials that include only participants focus more on the pediatric population, which increases the efficiency of the trial. Research indicates that the completion rate of randomized controlled trials involving children is significantly higher than that of trials involving adults or mixed groups of adults and children [37]. And the involvement of domestic sponsors may bring more resources and support, accelerating the trial process. On the other hand, MRCTs and trials with DMCs have relatively longer trial durations. This is because these trials involve more regions and institutions, and require more coordination and communication. The establishment of DMCs makes the data monitoring and examining process more rigorous and complex [38]. To eliminate these differences, researchers can strengthen collaboration and communication between multiple departments and regions, optimize data monitoring and examining processes, and improve trial efficiency to shorten durations [39].
New drug development is a lengthy, costly, and high-risk process, and the high discontinuation rate of clinical trials makes it the most challenging step in drug development. Compared to foreign countries, the main reasons for the discontinuation of trials in China are the safety or efficacy results (22, 27.2%) and commercial/trial plan adjustments (20, 24.6%) [11, 14, 40]. Discontinuation due to recruitment issues is infrequent, possibly linked to China’s demographic factors or sponsors’ limited scale and R&D capabilities. Tables 3 and 4 show that only small-scale pediatric trials with 0–50 participants may be discontinued early due to plan adjustments (17, 26.1%). This could be linked to sponsors’ R&D strategies and the impact of limited sample sizes on results [41, 42]. Placebo-controlled trials proved more challenging to conduct than active-controlled or single-arm studies, facing greater ethical scrutiny, operational complexities, and higher costs, which impeded recruitment. Furthermore, they were more susceptible to discontinuation based on interim safety or efficacy outcomes. Additionally, clinical trials incorporating DMCs are more prone to discontinuation, highlighting the critical role of DMCs in monitoring trial progress, safeguarding subject safety, and ensuring data quality. When potential risks or futility are identified, DMCs can swiftly recommend trial discontinuation, thereby preventing unnecessary resource expenditure and mitigating subject risks [38, 43]. A study showed that the use of DMCs was associated with possible risk factors for a premature ending and numerically, but not significantly associated with a premature ending [44]. Respiratory disease medications have low profits and numerous alternative treatments, leading to a decline in enterprise enthusiasm for research and development (4, 21.1%). There are significant differences in respiratory disease treatment methods between adults and children additionally [45], and this could be an influencing factor to the trial discontinuation. Pediatric oncology clinical trials are more difficult and costly (8, 36.4%), and the prevalence is low with most being rare diseases, making participant recruitment challenging (7, 31.8%). So the discontinuation rate for these two diseases is higher than other diseases [46]. With the implementation of implied license system and trial institution filing systems, more trial institutions and researchers have been attracted to participate in clinical research, injecting new vitality into drug development. However, the presence of multiple challenges, including the intricacies of conducting trials [47], the varying qualifications of trial institutions [48], challenge of data management and statistical analysis [49], and the scarcity of trial personnel [50], have made it difficult for some trials to progress smoothly. In recent years, the discontinuation rate of trials in China has shown an increasing trend year by year, with an average annual growth rate of 89.7%, which is a worrying phenomenon. Therefore, we still need to make continuous efforts to improve the regulatory framework and technical guidelines for trials, establish pediatric regional committees and data monitoring committees, and strengthen the cultivation of pediatric trial talents, in order to promote professionalization and standardization of pediatric drug clinical trials. At the same time, with the rapid development of artificial intelligence technology, clinical trials are also undergoing unprecedented changes [51]. AI not only optimizes trial design and improves the efficiency and accuracy of participant recruitment, but also shows great potential in predicting trial outcomes [52]. It is believed that with the advent of the era of personalized and precision medicine, pediatric drug clinical trials will no longer be an insurmountable challenge.
A limitation of this study is that ongoing pediatric drug clinical trials were not included. Additionally, due to the non-mandatory registration of clinical trial data on the Drug Clinical Trial Registration and Information Publication Platform before 2013, some trials that were not registered were not included in the study. This may have a certain impact on the research findings. Furthermore, due to the incomplete information of some registered clinical trials, it may lead to errors during the process of extracting data information.