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No child should die of cancer: paediatric oncology trials in Europe and USA

- José Matamoros Luna, Clinical Data Manager
No child should die of cancer: paediatric oncology trials in Europe and USA

Paediatric oncology has in general been one of the most successful areas of oncology where current treatments can achieve good efficacy and long term survival. However, this is still not the case for a significant number of children suffering from the disease. At the same time, paediatric oncology remains a complicated and challenging interdisciplinary field to perform successful clinical trials. Small patient numbers, potential toxicities, differences in tolerances towards treatment and high heterogeneity are just a small example of challenges that paediatric oncologists and drug developers face. Understanding the common practices and differences between study designs and regulations across the United States and Europe are important aspects to set up a successful paediatric oncology trial. 

Cancer is still the leading cause of death from disease in children, with a roughly estimated 10.000 and 35.000 newly diagnosed cases each year in the United States of America (USA) and Europe, respectively [1, 2]. Despite high incidence rates of paediatric cancer, the introduction of chemotherapeutics, radiation therapy and surgery has led to an 80% overall five-year survival. Latest estimates foresee that in Europe alone, the number of childhood cancer survivors will be half a million in 2020 [2]. This warrants to look into improvements of not only of current therapies, but also to focus on the long-term effects of cancer treatments in children.

SMS-oncology is already conducting paediatric oncology trials, which are being performed across 38 hospitals and institutes in Europe. The company has gained expertise in several processes on conducting clinical studies in children with cancer and is aiming to expand their knowledge. For this reason, we have performed a research project comparing the conduct and regulation of paediatric studies in Europe and the USA.


Study design: Europe versus USA

In order to investigate similarities and differences between the study design of paediatric oncology studies in Europe versus USA desk (literature and database) research was performed. Paediatric oncology studies, conducted between 2010 - 2016, were analyzed using a competitive intelligence database, called Globaldata [3]. The key difference identified between Europe and the USA was related to the childhood cancer types. In Europe, the focus appears to be on a single cancer type (Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia and Glioma) whereas in the USA, the majority of paediatric studies were focusing on multiple childhood cancers, meaning multiple single cancer types (i.e. multiple types of leukemia and lymphomas) investigated in one single trial (Figure 1). Interestingly also, in Europe more phase III (including phase II/III) paediatric oncology studies were conducted compared to the USA. In contrast, in the USA more early phase I paediatric trials were found to be conducted compared to Europe (Figure 2).

These findings have influence on the type of study design applied in the paediatric trials in the two geographical areas. In both continents, the majority of paediatric trials were found to be non-randomized, uncontrolled and applied a single group intervention, although, in Europe, more trials were as such compared to the USA. This is probably due to the fact that more late stage clinical trials are being conducted in Europe in contrast to the USA.

Finally, the dose-escalation designs that are used to investigate the optimal dose without causing severe adverse events, were compared. The majority of the paediatric trials did not contain a dose-escalation design. When this was used, the Rolling six design [4] was mostly applied. The Simon Two Stage design [5] was also prominent in early paediatric clinical trials. 

Regulations: Europe versus USA

The paediatric regulation in the USA was put into effect in 1998 and has now been split into two regulations, the Best Pharmaceuticals for Children Act (BPCA) [6] and the Pediatric Research Act (PREA) [7]. The Paediatric Legislation (PL) has been put in place in Europe since 2007 [8]. Both the PL and PREA are mandatory in Europe and the USA, and request a Paediatric Investigational Plan (PIP) or Paediatric Study Plan (PIP), respectively. These plans discuss the development and gathering of data on safety, efficacy and quality of a medicinal product for all paediatric population subsets. In Europe, the PIP needs to be discussed after the adult phase I pharmacokinetic studies and an agreement from the Paediatric Committee is necessary to obtain marketing authorization of the medicinal product. The procedure in the USA is similar, yet the PSP is discussed with the regulatory authority after adult phase II. The only exception in order to not file a PIP or PSP, is to request a waiver or deferral during the PIP/PSP submission process. A deferral is given when insufficient data is present to show efficacy and safety of the medicine in adults. A waiver is given when development of a medicine is not needed or appropriate, for example, when the disease only affects the adult population or is too toxic to be used in paediatric populations. 


The waiver system has had substantial influence in the oncology drugs made available for the paediatric population in both Europe and the USA. In Europe, the PDCO granted 9% of a total of 421 waivers towards oncology drugs while a proportion of them have been revoked since 2015, yet evident changes are not yet undertaken [9]. Another potentially valuable legislation in the USA, is the Research to accelerate Cures and Equity (RACE) for Children act. This act has been reintroduced in the House and Senate, making it possible for newly developed cancer drugs with relevant molecular targets in paediatric cancer, and leading to more paediatric oncology trials [10].

In the past decade paediatric oncology research has progressed with introduction of in depth legislation and execution of novel therapies consequently leading to the increased number of trials in paediatric populations. However, improvements (i.e. collaboration and alignment between stakeholders; more industry investments; better incentives) are still needed to increase the oncology drug development of which children can benefit from.


Paediatrics trials at SMS-oncology

SMS-oncology is currently performing several paediatric trials in Europe and is a strong advocate of closing the gap/imbalance for this underrepresented population. It is important to keep in mind that children are not ‘little adults’ and paediatric oncology trials requires specialized clinical and pharmacology expertise. At SMS-oncology, we want to offer our service in order to accomplish this mission, because no child should die of cancer.

Contact us to get in touch with our experts to discuss how SMS-oncology could support you for the best execution of your paediatric trial!




[1]: National Cancer Institute. Childhood cancer statistics USA. (2017). Available at: (Accessed: 7th April 2017)

[2]: The European Society for Paediatric Oncology. The SIOPE Strategic Plan; a European Cancer Plan for Children and Adolescents. (2015).

[3]: PLC, G. GlobalData PLC. (2017). Available at: (Accessed: 2nd February 2017)

[4]: Skolnik, J. M., Barrett, J. S., Jayaraman, B., Patel, D. & Adamson, P. C. Shortening the timeline of pediatric phase I trials: The rolling six design. J. Clin. Oncol. 26, 190–195 (2008).

[5]: Ananthakrishnan, R. & Menon, S. Design of oncology clinical trials: A review. Crit. Rev. Oncol. Hematol. 88, 144–153 (2013).

[6]: Food and Drug Administration. Best Pharmaceuticals for Children Act (BPCA). P.L. 105-115 111 Stat. 2296 (2002).

[7]: Food and Drug Administration. Paediatric Research Equity Act (PREA). P. L. 108-155. Stat. S 650 (2003).

[8]: Parliament, T. H. E. E., Council, T. H. E., The, O. F. & Union, P. The EU Paediatric Regulation 2007. (2006).

[9]: European Medicines Agency. 10-year Report to the European Commission: General report on the experience acquired as a result of the application of the Paediatric Regulation. (2016).

[10]: 115th Congress (2017). H.R. 1231 — 115th Congress: RACE for Children Act. 1–11 (2017).