Incidence of cancer in people aged 0-24 is low in comparison to incidence of adult cancers, and all individual cancer types that occur in children and young people can be classed as rare. As with all tumours with lower incidence rates, international clinical trials are a vital option to recruit enough patients to deliver results with the statistical strength to form an evidence base for a treatment.

As such, since the mid-2000s there has been a strong history of paediatric oncology driving forward international collaboration on clinical trials. Nevertheless, the discipline is not immune to the frustrations and barriers associated with running international trials.

Funding processes

International trials are not funded by one core source. Ordinarily each country running the trial is responsible for securing funding for its own set-up. In many cases, each country’s full participation in the study is required to meet the minimum recruitment numbers. If one funder withdraws, this can impact the entire trial, not just patients in that country.

In 2014, rEECur – an international trial investigating chemotherapy for Ewing sarcoma – opened its doors for patient recruitment with European Commission funding. By 2021 however, completion of European funding meant the trial ceased recruitment in several countries. Further funding was lost again in 2023. National funding streams were found to support the core clinical trial unit and ongoing recruitment in some countries and additional sites were opened across the remaining countries to compensate for the loss of recruitment. However, many of the original countries were unable to do this. While the trial has been able to continue, the loss of major recruiting countries has affected the whole trial. This demonstrates just how vulnerable an international trial in a rare cancer can be to funding decisions across international borders.

And it’s not just the removal of funding that can be an issue, the timing of it can also be difficult to navigate. Researchers in the US and many European countries often receive their funding at a much earlier stage in the process than those in the UK.

Dr John Moppett is a consultant Paediatric Haematologist at University Hospitals Bristol NHS Trust and the lead investigator on ALLTogether-1, a trial investigating more personalised treatment approaches for acute lymphoblastic leukaemia (ALL). “The US gets their money first and then they have 12 months to get the trial opened – which is the point that we in the UK have something to approach funders with,” he explains. “It then takes the best part of nine months to get through the application process, and then another 18 months to two years to go through ethics and other approvals.”

Legislation, regulation, and bureaucracy

Even when adequate funding is secured across the countries involved in the trial, designing one that complies with the range of regulatory requirements and processes represents a further challenge. Regulations surrounding trials can vary greatly between countries, making it difficult to write protocols that are internationally compliant. Even small matters of wording can throw up issues which, in the case of the Belfast site for ALLTogether-1, can turn into years-long delay to opening.

As part of the trial, some European countries wanted to be able to run a multigated acquisition (MUGA) scan – a test that uses ionising radiation to scan the heart. In the UK, heart scans would be completed via an echocardiogram; but the trial protocol included wording that sites ‘may’ optionally run a MUGA. The trial also discusses the optional use of CT scans, which of course also expose patients to ionising radiation.

“There isn’t anything that requires additional ionising radiation in our trial. The protocol doesn’t say you have to do a MUGA or a CT scan, but there’s an option to,” says Moppett. “That means it’s got to go through a specific assessment – which is constrained by the fact there’s not enough radiologists to do it. That caused a real delay, yet it’s a test they don’t need to do.”

While these issues represent long-standing barriers, the bureaucracy associated with international trial set-up has been compounded since the UK left the EU. The EU no longer “recognises” UK sponsors of clinical trials and there is no mutual recognition of medicines “batch testing” processes. This creates extra costs and red tape. And as the UK is not part of the Clinical Trials Information System (CTIS), the regulatory process for clinical trials in the EU, this means yet more duplication. “We used to have a single, combined regulatory application process, which we’re now outside of,” explains Moppett. “That makes it more complicated.”

The paper exchange involved in the process also throws up further risks.  Professor Bernadette Brennan is a Consultant Paediatric Oncologist at Royal Manchester Children’s Hospital and lead investigator on INTER-EWING-1, an international trial investigating treatment for Ewing sarcoma in children and adults. “Each individual centre from each country – and there can be hundreds in the study – has to send masses of paperwork,” she says. “You just have to miss one document, and it causes delays.”

“The main drug is made in the European Union, so we have to import it,” Moppett says. “We’ve had various issues with customs documents not turning up in time, so there’s gaps where the drug isn’t available.”

Shipping tissue samples across borders presents further issues. “We can’t ship samples to the lab in Copenhagen for analysis in real time, because they’ll get stuck in customs and become useless,” explains Moppett. “The only solution is to store the samples in freezers at Great Ormond Street and ship them in bulk. Even after reductions it’s still several hundred samples, and at a cost of £42 per sample to store in this way, we’re going to spend several thousand pounds just because we can’t ship them in a timely fashion.”

All of these barriers delay the core work of the trial, increasing the overall cost of the research, with multiple impact points. Research teams are constrained on where they are able to apply for funding, as smaller funders are unable to meet these costs. The increased expense also represents a significant opportunity cost in terms of the research that could have been funded. This is especially important given the market failure around the development of new therapies for children and young people’s cancer has led a lack of investment from the pharmaceutical industry.

Ultimately, any delay to a trial opening is a delay to the time that patients can start receiving treatment; or increases the risk of a trial failing altogether.

What is being done to address this?

A huge majority of the childhood cancer trials led by Cancer Research UK-funded Clinical Trials Units are international; and for many childhood cancer types, the only progress made to date has been through international trials.

Addressing barriers to international trial set-up is imperative to continuing progress for children and young people, and there is no one solution that can address all of these issues. But as Moppett highlights: “if we can make a 1% improvement here and a 1% improvement there all of a sudden we have a 10% improvement – and that’d make things a lot better.”

Charities and funders are working to highlight these issues and convene stakeholders to take action. In April, Cancer Research UK released a policy report highlighting how the new UK-EU relationship can best support international collaboration in cancer research. CRUK is also currently running an engagement programme on international research collaboration with the UK Government and EU institutions. It’ll involve people affected by cancer, the research community and policy partners within and beyond the UK, as it makes the case for reducing barriers to clinical trials and the UK’s involvement with global research funding programmes, such as Horizon Europe.

Organisations concerned with children’s and young people’s cancers are also working together to address issues around trial set-up time. Solving Kids’ Cancer UK launched the Initiative for Multi-stakeholder Partnership to Accelerate Children’s Cancer Trials (IMPACCT) to convene research and healthcare professionals, Clinical Trial Units, national research networks, trial delivery experts and other stakeholders to develop practical solutions to speed up trial implementation.

Thanks to research, children’s cancer survival has more than doubled since the 1970s in the UK. But while survival has improved, cancer remains the leading cause of death by disease in children and young people over the age of one, and survival for some children’s and young people’s cancers hasn’t improved much in the last 50 years.

Creating a research environment that fosters international collaboration is imperative to ensure that more children and young people live longer, better lives, free from the fear of cancer.