In Spain, a new case of cancer is diagnosed in 1 out of 6,500 children aged less than 15 years every year. This amounts to 1,100 new cases in children aged 0 to 14 years, while there are 450 in adolescents aged 15–19 years.1

There have been enormous medical and therapeutic advances in paediatric cancer. In Europe, the mortality associated with childhood cancer decreased by 60% between the 1950s and the 1990s.2 These figures have continued to improve since, although there has been a plateau in some diseases.1 In Europe, the overall 5-year survival for all types of cancer diagnosed between 2000 and 2007 was 77.9%.3 This success is due in large part to the development of multicentric clinical trials conducted by collaborative research groups.4

However, cancer continues to be the leading cause of death by disease from the first year of life and through adolescence1: in 2014, cancer caused 29% of deaths in children aged 1–14 years, and 20% of deaths in adolescents aged 15–19 years.5

More specifically, the prognosis of certain diseases continues to be bleak, for instance in metastatic medulloblastoma, sarcoma or neuroblastoma, high-grade glioma or in patients with other types of cancer that recurs or is refractory to first-line treatment.

Thus, there is a pressing need for new drugs.

These novel anticancer drugs are needed to improve survival and reduce the sequelae that result from multimodal treatment combining surgery, radiotherapy, chemotherapy and haematopoietic stem cell transplantation. Recently, the identification of particular molecular changes in specific tumours has led to the development of targeted therapies against them, which has come to be known as “precision medicine.”6 This has opened the door to strategies adapted to the presence of molecular changes or immunotherapy at the time of diagnosis or relapse, which are exclusive to oncology patients.

There is evidence of the usefulness of new targeted therapies in some paediatric solid tumours: ALK inhibitors for anaplastic large-cell lymphoma,7,8 Sonic-hedgehog signalling pathway inhibitors for medulloblastoma9 or BRAF inhibitors for high-grade glioma in patients with BRAF-V600E mutations.10,11

In leukaemia, the best 2 examples correspond to chronic myelogenous leukaemia and acute lymphoblastic leukaemia, in which the discovery of the Philadelphia chromosome (t(9;22)(q34;q11)) allowed the identification of the BCR-ABL fusion protein, which plays an essential role in their pathogenesis. This finding has allowed the development of drugs such as imatinib, dasatinib or nilotinib that can kill leukaemia cells through the inhibition of ABL kinase activity, improving the prognosis of these patients.12,13

Thus, continued investment in research and development of novel anticancer agents for paediatric cancer is of vital importance.

Motivated by the dearth of paediatric data for already authorised medicines, new legislation was introduced in Europe in 2007 regarding the regulation of medicines in paediatrics that refers to the “paediatric investigation plan” that pharmaceutical companies need to submit to the European Medicines Agency at the time of applying for authorisation of a new drug.14 Thus, whenever a pharmaceutical company gets a new drug authorised (usually for the adult population), it must be accompanied by a plan for paediatric development (as long as the drug is potentially useful in children). When paediatric investigation plans are completed satisfactorily, the medicine is eligible for a 6-month supplementary protection certificate, or in case of a so-called orphan medicinal product, for an extension of 2 years to the 10 years of market exclusivity for the already authorised indication.

The aims of this measure are15:

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  To increase availability of new medicines authorised for use in children through generation of accurate safety and efficacy data and high-quality ethical paediatric clinical research

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  To produce better information on existing paediatric medicines.

Despite the introduction of these initiatives in Europe in the past 15 years, the development of novel drugs for the treatment of paediatric cancer is still insufficient: 14 out of the 28 anticancer agents approved for adults have been waived for paediatric development, while 26 of them were relevant to childhood cancers.16 Thus, it is necessary for representatives of academic institutions, regulatory bodies, the pharmaceutical industry, parent organisations, patient rights advocacy groups and other charities to continue working and collaborating closely to facilitate children access to these new drugs.16

Generally speaking, the use of certain drugs in patients with refractory or relapsed cancer is not based on a solid foundation of scientific evidence, and most are not indicated for the paediatric age group. The off-label use of drugs that are only authorised in adults carries significant risks and does not help improve the scientific evidence on their use.17

Traditionally, the development of a new drug involves different phases (I through III) to evaluate its toxicity and safety (I), efficacy (II) and improvements in survival (III) in specific populations.18 Phase IV trials are postmarketing studies that seek to identify toxicities that were not observed previously and assess long-term efficacy. When it comes to oncology, the subset of patients that participate in early-phase trials (I and II) mostly consists of those who have relapsed after at least one course of treatment, or with refractory cancer. This is a long and costly process—usually more than 10 years from target identification in a laboratory to marketing with costs of up to 2000 million dollars per product.19 Fewer than 5% of medicines evaluated in phase I clinical trials gain market authorisation,20 and only 1 out of 10000 compounds ever reach the market.21

Along these lines, the Innovative Therapies For Children With Cancer consortium (ITCC; http://www.itcc-consortium.org) is an international organisation whose principal aim is to evaluate novel therapies for the treatment of cancer in children and adolescents. The ITCC provides the necessary accreditation to develop and implement clinical trials in childhood cancer, facilitates contact with academic or pharmaceutical industry sponsors, and opens new clinical research centres22 with the purpose of expediting access to these medicines for children.

The aim of this study is to describe the activity in early-phase clinical trials in paediatric cancer in Spain in the past 10 years, to evaluate the hurdles that we are facing, their potential solutions, and future challenges. This study will provide a reference for this field for future comparison, following the example of the BEST project of Farma Industry, an association that seeks to promote excellence in clinical research of medicines in Spain and to assess performance, efficacy and quality in the field (www.farmaIndustry.es).

The Sociedad Española de Hematología y Oncología Pediátrica (Spanish Society of Paediatric Haematology and Oncology [SEHOP]; www.sehop.org) represents all paediatric oncology units in Spain. We contacted all the SEHOP members to identify phase I and II trials for solid tumours and blood cancers initiated between 2005 and 2015. We chose this period because in Spain, early-phase trials in the paediatric population started to be conducted in 2005.

For each of the trials, we collected data regarding the type of trial (phase I or II), sponsor (academia or pharmaceutical industry), number of participating centres, enrolment period, type(s) of tumour(s) under study, drug under investigation, mechanism of action and number of patients enrolled in the trial. We updated these data on December 1, 2015. We checked whether trials were still recruiting patients in June 15, 2016.

When further information was needed, we resorted to the clinical trials registry of the United States National Institutes of Health (www.clinicaltrials.gov), the European Union Clinical Trials Register (www.clinicaltrialsregister.eu) and the Spanish Register of Clinical Trials of the Agencia Española del Medicamento y Productos Sanitarios (Spanish Agency of Medicines and Medical Devices [AEMPS]; https://reec.aemps.es).

This article describes the activity in the development of new treatments for paediatric cancer in Spain.

Children with cancers that are high-risk or carry a poor prognosis continue to have difficulty accessing new drugs. The number of trials opening in Spain has increased in the past 5 years, probably as a result of hospitals joining the ITCC, changes in legislation applying to paediatrics and institutional efforts to establish units devoted to these trials staffed by physicians, research nurses, project managers and data managers.

Between 2010 and 2014, 4 centres have joined the ITCC, a consortium established in 2003 that comprises 9 European basic research laboratories and 47 paediatric oncology centres with the necessary resources to carry out phase I and II clinical trials in paediatric oncology. One of the aims of the consortium is to develop novel therapies for paediatric malignancies in collaboration with pharmaceutical companies, regulatory bodies and patient and parent associations.22 Since 2007 the number of drugs in early phase trials being run by the ITCC has grown from one in 2007 to 12 in 2013, with half of these trials being conducted to comply with the regulatory requirements of a paediatric investigation plan; this has significantly improved access of European children to novel therapies.15 For Spain, being actively involved in the ITCC allows us to participate in international collaborative trials, which facilitates access to promising therapies to our patients.

Most of the early-phase clinical trials in paediatric oncology and haematology that have opened in Spain have been sponsored by the pharmaceutical industry (n=16; 53%). Only one third of the total focus on blood cancers. This is possibly due to the fact that the overall cure rate with first-line treatment is high for leukaemias and lymphomas, and that a significant percentage of patients that relapse achieve full remission for the second time and eventually a cure with conventional chemotherapy or haematopoietic stem cell transplantation. Thus, the target paediatric population for new drugs for blood cancers is smaller. Recruitment is further complicated by the stringent inclusion and exclusion criteria, the challenges involved in transferring patients from their original hospitals to the centres where these new therapies are available, and the natural history of the disease, which sometimes does not allow delays in treatment initiation. These factors also apply to solid tumour patients, and in specific nervous system diseases or sarcomas, there are even fewer clinical trials.

For all the above reasons, paediatric cancer as a whole constitutes a “small” market with few incentives for the pharmaceutical industry.32

We believe that these groups of “orphan” patients should benefit from academic clinical trials. From our paediatric haematology and oncology society,33 and in collaboration with other scientific societies, such as the Grupo Español de Investigación en Sarcomas (Spanish Sarcoma Research Group [GEIS]), we aim to develop and participate in collaborative academic clinical trials to promote therapeutic advances and the optimisation of existing therapies for rare diseases like childhood cancer, which are not usually the target of pharmaceutical companies. Our duty as researchers is to improve on study design to add adaptability and flexibility, and to develop trials on the basis of solid scientific evidence so that they target populations that are more likely to show a favourable response.34 In this regard, the Sociedad Española de Oncología Médica (Spanish Society of Medical Oncology) took an important initiative in addressing a manifesto to policymakers requesting support for independent academic clinical research.35

An added difficulty is the lack of funding for clinical development in academic settings. This poses barriers to participation in international academic clinical trials, as the costs of opening the trial at the local and national levels must be assumed nearly in full by participating countries. Few not-for-profit organisations fund paediatric cancer research programmes or have specific agendas to support clinical trials. The recent Royal Decree 1090/2015 regulating drug clinical benefits non-commercial clinical research studies through exemption of fees or reduced fees and by simplifying the costly and complex bureaucracy involved in opening such trials. Lack of funding does not only ail this side of the Atlantic. In the United States, 60% of the funding for biomedical research comes from the biopharmaceutical industry,36 followed by the National Institutes of Health, which contributes another 25%. However, funding from the pharmaceutical industry is nearly nonexistent in paediatric cancer, so that research in the field depends on the National Institutes of Health, private institutions and charities.32

On the bright side, the favourable outcomes observed in samples selected based on molecular findings and treated with targeted therapies such as ALK or BRAF inhibitors8,10,11 or with the use of anti-GD2 mAb in high-risk neuroblastoma26 are encouraging, so we must remain optimistic. Such evidence ought to stimulate investment in basic and clinical research and help patients be referred more easily to centres that can offer new therapies that may be beneficial.

The experience of 2 or the largest early-phase clinical trial units in paediatric oncology in Europe, the Royal Marsden (London, United Kingdom)37 and Gustave Roussy (Villejuif, France)38 proves that implementing these therapies in the context of everyday paediatric oncology practice is possible and safe for patients, while allowing a significant percentage of paediatric cancer patients to benefit from these treatments.

Clinical trials are a necessary and indispensable means to evaluate new treatments that can provide robust and solid data on their safety and efficacy, which is as beneficial to the scientific community as it is to patients. The evaluation of new anticancer drugs in children and adolescents must comply with current legislation, avoiding off-label use17,39 and in the context of clinical trials approved by ethics committees and conducted in adherence to good clinical practice principles.

The authors have no conflict of interests to declare.