Cancer drugs for children

Developing drugs specifically for children is associated with ethical, practical and financial problems. But new drugs are needed, not least to save the 20 per cent of children with cancer who are still dying today. Optimism is now growing thanks to a new attitude to the task at hand.

Text: Fredrik Hedlund, first published in the magazine "Medicinsk Vetenskap" no 3, 2016.

Professor Per Kogner. Photo: Ulf Sirborn

Is the glass half full or half empty? It’s a classic question of perspective. Our knowledge and our ability to treat children with drugs has never been greater, but is it good enough?

In terms of cancer, which is the illness that most children in Sweden die from, the glass is definitely more than half full. In one generation, survival rates following treatment have gone from almost zero to an average of 80 per cent. At the same time, however, there are those who say that there has been too much of a focus on the positive developments and the 80 per cent who survive and not enough on the 20 per cent who do not.

“These days, the children who do not survive have tumours with more challenging and complicated origins and greater resistance than the 80 per cent that we are able to help,” says Per Kogner, Professor of Paediatric Oncology at Karolinska Institutet. “That final 20 per cent require a huge amount of additional biological knowledge and international collaboration.”

Up to now, paediatric oncologists have had to content themselves with the cancer drugs that have been developed for adult use and with optimising their use in treatment for children. But childhood cancer and adult forms of cancer are not the same, and in order to cure the final 20 per cent there is a need for fundamentally new drugs that can strike at the specific biological systems of these tumours. However, this is where it gets difficult.

Drug development is very expensive, and the high cost of development combined with the relatively small numbers of childhood cancer patients make it difficult to justify as a business venture. It is also more difficult, in both ethical and practical terms, to carry out studies on children than on adults.

So paediatric oncologists such as Kogner are realistic about the likelihood of the new drugs that are needed being produced.

“Developing a drug from start to finish for a biological mechanism in childhood cancer that doesn’t exist in adult forms of cancer – I have very little hope of that,” he says.

The difficulties involved in testing drugs on children means that they have very rarely been studied as part of a drug development process. This has of course had consequences for children’s treatment.

“Most of the drugs we use on children are not indicated for children in the Fass database of information on medicines,” says Kogner.

In Sweden, doctors are allowed to use drugs outside the approved indication if they themselves take personal responsibility. And over time, of course, they accumulate knowledge about how to use them, but with new drugs there is usually neither scientific evidence nor experience. Instead the first child patients become guinea pigs for the treatments.

In 2007, the EU tried to address this by introducing new legislation taking a carrot-and-stick approach to encourage companies to undertake more trials on children. In simple terms, the law says that there must be trials on children for all new drugs unless there are no obvious reasons not to, for example if a particular illness does not exist in children. As a carrot to encourage trials on children, the term of the company’s patent is extended by six months and they thus get an extended period of exclusive rights for their drug on the market.

But the outcome has not been as hoped. In all too many cases, the countries have been given a dispensation by the European Medicines Agency and have

not had to carry out child drug trials. According to European childhood cancer organisations, six out of ten potentially valuable new cancer treatments have been exempted from the rule that trials on children must be undertaken. In many cases, the companies have pointed out that the cancer in question is not found in children. One example is a relatively new medicine for a type of lung cancer with a specific mutation. Lung cancer does not occur in children, and so child drug trials were not needed. But that mutation was shown to exist in certain other childhood cancer tumours, which Kogner and his colleagues are now successfully treating with the lung cancer drug.

“It’s like having the key that fits the lock,” he says. “The children are cured without side effects.”

But he is obliged to take personal responsibility for the use of the drug because no trials have yet been completed and nor is there approval for use on children.

According to Richard Bergström, former Director General of the European Federation of Pharmaceutical Industries and Associations (EFPIA), there are many reasons why the pharmaceutical industry is reluctant to test new cancer drugs on children. One of the most significant is that the industry does not yet have the set-up required to study a small number of patients in a great many different places across Europe, which is something often needed in order to bring together a large enough group of child patients.

And then there is the issue of whether the extended patent is enough of a carrot for the drugs companies. The normal lifespan of a drug has traditionally been 10-15 years, during which time the company is expected to recoup the cost of developing the drug and ideally make a profit. But the recent upsurge of new cancer drugs in recent years means that calculation no longer adds up.

“With cancer, you can very clearly see that products that only came onto the market a few years ago are no longer being used,” says Bergström. “A drug’s lifecycle is often extremely short, and so the question is what the additional patent is worth after 15 years if the drug is no longer in use.”

But a group of European childhood cancer organisations has now created a research platform called Accelerate, which aims to try to get around the obstacles that make the development of new cancer drugs for children so difficult. The thinking is that with better knowledge of the biology of childhood cancer tumours that are difficult to treat, it will be possible to identify likely candidates from amongst the substances that are already in the drugs pipeline and channel them through for trials on children.

The organisations have managed to persuade major pharmaceutical companies, including AstraZeneca, Boeringer Ingelheim, Bristol-Myers Squibb, Genentech, Hoffman-La Roche and Novartis, to invest in the venture, open up their archives and share their data. The Accelerate group will together evaluate the whole drugs pipeline and jointly select the best, most promising candidates to go forward with. This will avoid the relatively small number of childhood cancer patients being used in trials of less promising treatments. The group published its joint declaration of intent just before summer 2016. And although the task may seem to be verging on the impossible, there is no doubt that reaching an agreement around this has kindled hope of saving the final 20 per cent of children who currently do not survive.

“If we can have a vision of zero traffic fatalities, we must surely be able to have a vision of zero deaths from childhood cancer,” says Kogner. “We need to stop thinking that the impossible is impossible – it’s simply a little bit harder. It needs more time, more money and more investment in research.”

The fact that pharmaceutical companies have suddenly agreed to be more open, share their data and allow outsiders to have a say on their drugs pipeline is a state of affairs that most people would have thought impossible ten years ago, but it appears to be part of a whole new strategy in the cancer field.

“When I meet my research directors, this is one of the things they talk about a lot,” says Bergström.

He explains that the rapid developments in the field of adult cancer, with treatments increasingly becoming specifically targeted, also mean that the number of potential patients for each treatment is declining. This is a problem that childhood cancer has been struggling with for some time and which is now starting to be resolved.

“The idea that’s emerging is not just to organise research into childhood cancer in this way but to do so for all types of cancer,” says Bergström. “That’s what I’m hearing from my more progressive, radical industry colleagues and also from the oncologists.”

And that development appears to be underway in the United States already. At the start of the year, President Obama initiated his ‘Cancer MoonShot 2020’ programme – an initiative as bold as the moon landing in 1969 – aimed at developing new cancer treatments by 2020. The project is a collaboration between pharmaceutical companies, academia, authorities, doctors, insurance companies and the US government who will share information and together drive research forward. The work is being led by Vice President Joe Biden and involves a multibillion investment in cancer research.

Both the American and the European collaborative investments in the development of new cancer treatments are good news for any children diagnosed with cancer in the future. Working together, there is a greater likelihood of finding a cure.

Swedish paediatric oncologists are now also being given an opportunity to contribute to this work. One of the childhood cancer organisations behind Accelerate is Innovative Therapies for Children with Cancer (ITCC), a consortium of European paediatric oncologists established in 2003. The aim is to facilitate clinical evaluation of new substances to combat childhood cancer, and part of that work is to create a European network of skilled research clinics. This is something that the pharmaceutical industry says is lacking and will make it possible to conduct trials on children.

Sweden has not previously been involved in this European project, but in April this year the country’s first centre for the clinical testing of drugs for children with cancer – HOPE – opened at the Astrid Lindgren Children’s Hospital in Stockholm. The testing unit was founded by two parents whose three-year-old son died from a brain tumour in 2013 and so set up a foundation to raise money and establish HOPE. The main purpose of the unit is to enable more Swedish children to have access to new drug treatments that are in the testing stage, but it also allows Sweden to become a member of ITCC and be part of the promising developments in new cancer treatments for children. Despite this, HOPE does not yet have secure funding. It is currently being run on donations, mainly from the parents themselves, who have given SEK 1.5 million, and from the Swedish Childhood Cancer Foundation. According to the foundation’s calculations, SEK 7 million is needed to be able to operate the unit at a basic level for another three years and a total of SEK 20 million to enable the unit to become self-supporting in five years.

What is perhaps most surprising is that it has needed action by broken-hearted parents channelling their frustration to get Sweden to take the step of joining ITCC.

“Various decision-makers have not pushed sufficiently for Sweden to become a member of ITCC, but now we are finally in,” says Kogner. “HOPE is a valuable resource that makes important clinical trials possible. And only clinical trials of biologically-based treatment will help us get closer to our vision in which no child with cancer has to die.”

New cancer drugs are seldom tested on children

In 2007, the EU introduced a new legal requirement for all new drugs to be tested on children. The European Medicines Agency can, however, make exceptions for drugs that are indicated for conditions that do not occur in children or that may be presumed to be ineffective or unsafe or no better than existing treatment.

To date, over 60 per cent of the 89 potentially interesting cancer medicines that have been developed since 2007 have been exempted from the legal requirement to be tested on children.

European Journal of Cancer, July 2016.

Why developing drugs for children is difficult

Ethical challenges
Trialling drugs on people unable to make their own decisions about participating in trials is a particularly sensitive issue. This means that the ethical requirements for trialling drugs on children are extra stringent.

Few patients
It can be difficult to find enough children with a particular illness and of a particular age to put together a trial that you can draw reliable conclusions from.

High costs
It takes about 15 years to develop each drug and costs on average over SEK 10 billion. The small number of patients makes it difficult for pharmaceutical companies to recoup the development costs of their drug. In order to balance their books, they have to demand a very high price for each treatment.