As we mark International Childhood Cancer Day on 15 February, it is important to note that globally, childhood and adolescent cancer is threatening to overtake infectious diseases as one of the leading causes of disease-related mortality in children.

The lack of pharmaceutical industry investment in addressing therapeutic needs of childhood disease has long been recognised as an issue. Consequently, a new European Union paediatric medicines regulation was implemented in 2007.

This incorporated a system of legal obligations and financial incentives for the industry to ‘improve the health of children in Europe by facilitating the development and availability of medicines for children aged 0 to 17 years’.

Over a decade later, the European Commission has published the ‘State of Paediatric Medicines in the EU – 10 years of the EU Paediatric Regulation’ report – clearly identifying the failure of this legislation to benefit children with cancer. Frustratingly, the report does not propose any immediate improvements to the legislation.

As we today mark International Childhood Cancer Day we need to ask, why are the current innovations in cancer medicines not reaching children? The pace of clinical drug development for children with cancer is substantially lagging behind the accelerated changes we see for many adult cancers.

The Regulation introduced in 2007 proved a successful driver to increase the access to new medicines for some childhood diseases, but for cancer, paediatric drug development remains inextricably linked to the lucrative market potential for adult cancer indications.

The balance between the high level of investment needed to deliver a fully executed Paediatric Investigation Plan (PIP) – in accordance with the 2007 legislation – and the potential financial reward is not proving sufficiently attractive to encourage the pharmaceutical industry to adequately invest in drug development for childhood cancers.

This matters because childhood cancer remains the leading cause of disease-related death in children under 16-years-old. Moreover, for those children that survive, up to 40 per cent have long-term side effects as a consequence of treatment. More effective and less toxic medicines are long overdue.

A major weakness of the 2007 Regulation is that it allows waivers to the obligation of conducting a PIP to be granted, resulting in significant lost opportunities for children with cancer.

Between 2012 and 2015, waivers were granted for 89 cancer drugs. We estimate that 54 per cent of these drugs had the potential to benefit childhood cancers based on the scientific rationale of how the drug works; its ‘mechanism of action’ (MOA). A waiver can be awarded if the clinical indication for which a medicine is being developed does not occur in childhood; for example; prostate cancer.

However, in an era of modern, biology-driven medicine, drugs are often developed to inhibit a molecular driver of cancer and that target can be of relevance to multiple cancers, including cancers occurring only in childhood.

A frequently quoted example was the waiver awarded for the development of crizotinib, a drug targeting a protein call ALK (Anaplastic large cell Lymphoma Kinase) towards marketing authorisation in lung cancer. This was in the face of substantial published evidence for the scientific rationale to target ALK in multiple childhood cancers. The waiver meant that the drug proceeded to market in lung cancer with no obligation to investigate the drug’s potential therapeutic benefit in relevant childhood cancers; this was an unacceptable lost opportunity.

Multiple stakeholders have called for cancer drug development to be on the basis of the mechanism by which the drug worked rather than the type of disease for which a licensed indication is sought.

The European Commission’s ten-year report recognised this flaw in the 2007 Regulation but disappointingly failed to recommend the legislative changes needed to correct it, expressing concern that an ‘MOA model could impact upon the predictability of the scope of a paediatric development plan and may lead companies to reconsider the overall product development’.

In sharp contrast in the US, the FDA Reauthorization of the Research to Accelerate Cures and Equity (RACE) for Children Act was passed in August 2017, which requires companies to undertake studies in children when the molecular target of their drug is relevant to a childhood cancer.

The European Commission intends to undertake further reviews of the legal frameworks in Europe that impact on diseases which occur only in children, aiming to ‘support medicine development in subpopulations with particular needs’ providing results by 2019, with the aim of informing the next Commission’s policy options. Altogether, this two-year process will further delay improvements of the European regulatory environment for drug development for childhood cancer. Patients, parents and physicians, amongst other stakeholders, will continue to lobby for accelerated change in policy on this pressing issue.

Professor Pamela Kearns
Honorary Consultant in Paediatric Oncology, Professor of Clinical Paediatric Oncology, Institute of Cancer and Genomic Sciences, University of Birmingham