Specific needs for pediatric clinical trials

The implementation of a pediatric trial presents various challenges, such as the recruitment of patients and the obtaining of informed consent. Parents are naturally concerned for their children's well-being and are reluctant to enroll them for a research project whose future use in children or adolescents is unknown. Moreover, disease prevalence in the pediatric population is also different to that in the adult population, e.g. congenital and rare diseases are more of an issue.

The conduct of pediatric clinical trials requires special needs compared to adult clinical trials:

Children are not small adults.

Unique rare diseases in pediatrics constitute a sizeable and increasing proportion of pediatric morbidity and should not be neglected: they are of extraordinary scientific interest, and new approaches to treatment are emerging rapidly. Thus, a pediatric network must have appropriate facilities to deal with children and their families, be well linked to support studies of medium to low incidence, and yet have a degree of collaboration and central coordination that is proportionally higher than that required for adult medicine.

Longitudinal trials are needed, since the majority of pediatric diseases have a strong developmental component. To address this, long-term studies and database structures are needed to prospectively assess long-term outcomes. Again, coordinated national efforts are needed in order to establish such long-term studies, databases, and biobanks.

The lack of age-related normative data in pediatrics as well as from healthy control groups is huge. Only systematic, prospective observational studies in healthy volunteers can provide a real basis for the recognition of abnormalities in pediatric disease. In order to build up healthy reference cohorts for the Swiss population, coordinated efforts and biobanks, managed within a network of coordinated pediatric centers, are urgently needed.

Special facilities for clinical trials in children are necessary, i.e. specialized knowledge is required in study design, focusing on particularities, such as noninvasive diagnostic techniques and age-related feasibility, as well as a clinical research environment that is appropriate for this young age group. For example, studies in infants can only be done with specialized nurses and doctors in an environment connected with neonatal units, so as to maximize safety.

Safety and monitoring requirements for clinical trials in children are high. Infants and children below 14 years of age have limited insight into and understanding of the study purpose. Thus, it is particularly important that ethical considerations, safety, and the monitoring of trials are of an even higher standard than those in adult studies. Particularly in multicenter trials, substantial personnel and structural resources are required. Thus, for example, coordinated support of ethics proposals in multicenter pediatric studies could greatly facilitate clinical research in this field.

Coordinated teaching in clinical pediatric research: The use of good clinical practice (GCP) guidelines should be specified in a pediatric context. Such efforts should be coordinated.

Public awareness of, and political support for, the needs of pediatric research: There is no institution specifically advocating the needs of children in Switzerland, and this is particularly evident when attempting to access funds for pediatric research.

A pediatric-specific hub for European pediatric networks: Pediatric networks are starting to evolve in Finland, Germany, and other countries in Europe, facilitating multinational research. To be attractive and competitive for international funding agencies and international companies, it is necessary to establish network structures that fully satisfy the needs of the European Enpr-EMA network.

Pediatric-specific hub for industry-sponsored Phase 1—3 drug trial: Despite higher trial costs, Switzerland is still an important partner for clinical research, due to the quality of patient and data management, and local specific knowledge. However, industry partners have clearly indicated that Switzerland can only be competitive if coordinated multicenter studies can be performed. Therefore, there is an urgent need for a coordination office, which can be used as a hub and coordinator for industry partners.

Clinical research in children

It is particularly true in pediatrics that rare diseases, congenital or acquired, often allow for exceptional insights into pathophysiological mechanisms that apply to adult patients as well; in fact, the adult patient and his physician profit from what has been learned in the sick child more often than the other way around. Many chronic diseases originate in early childhood, and long-term observations and longitudinal pediatric cohort studies contribute greatly to the understanding of disease evolvement. Furthermore, there is increasing evidence that early infancy is a vulnerable developmental phase when many biological systems are still developing and organs finalize their development. Known as the Barker Hypothesis, during these early phases of life many environmental factors modify and program normal and abnormal development respectively. A better understanding of the processes involved in this early organ development provides unique opportunities for early disease recognition using novel biomarkers and, subsequently, early preventive and therapeutic strategies. The latter are the basics for the emerging field of personalized medicine in pediatrics.

Preventive strategies and drug development in pediatrics

Consideration of novel findings in the management of patients is essential to the process of improving distinct aspects of medical practice, including prevention, diagnosis, management, and outcome of diseases. However, both translational research and consideration of novel findings require the installation of clinical trials to efficiently impact on the progress of medical care. Unfortunately, from the perspective of pediatricians, there is a large gap in the availability of thoroughly studied and licensed diagnostic or therapeutic means for children as compared to adults. Results from studies in adults can rarely and, if so, only barely be transposed to neonates, toddlers, children, or adolescents because of the huge biological differences. Moreover, a large number of diseases exist that are either childhood-specific or have their onset in the pediatric age range impacting development and growth. “Lack of evidence” for the pediatric age range is a frequently cited reason to withhold treatment that might appear promising on theoretical grounds. Pharmaceutical companies are less than enthusiastic about sponsoring pediatric trials, as the technical requirements are more complicated, the potential market is smaller, and children need special pediatric formulations to meet the different body weight class and appropriate administration route requirements. As a result, children and adolescents do not have the same access to newer medications or treatment modalities, and a large number of drugs are administered to children in the absence of formal evidence of efficacy and/or a recognized indication (known as off-label use).

There is an unmet and urgent need for pediatric clinical trials to advance and improve patient care in pediatrics. The Swiss National Science Foundation (SNSF) has recently proposed as part of its long-term strategies to address so-called "orphan diseases", those rare disorders that have difficulties finding other funds but significant clinical and health-economic impact. Studies in pediatrics clearly meet this focus, particularly when their long-term impact is considered. Investing in research in pediatrics will clearly have a sustained effect for generations to come.

Clinical trials are needed to generate age-specific safety and efficacy data, as well as evidence on distinct medical procedures. They are not restricted to the study of novel drugs but have a wide spectrum of applications, including the study of complex disease mechanisms and the many facets of optimal patient care. The clinical trial is the crucial final step in translational research and is one of the most important, and most widely used, tools of medical research today.