It’s about acceleration

Professor Pam Kearns talks frankly about clinical trials and children’s cancer.


If you search on Facebook, you can find a picture of Pam Kearns with ‘the girl whose life she helped save.’ In the photograph, doctor and patient share a relaxed smile and an obvious affinity. Pam was Paige’s clinician after the 11 year-old fell ill with Wilm’s Tumour, a rare form of kidney cancer. However, the role she plays in helping children like Paige is not just that of providing treatment. She is Director of Cancer Research UK’s Clinical Trials Unit and a leading figure in the search for new ways to combat paediatric illnesses like Wilm’s.

Paige’s story is a heartening one but if you go to hear Pam speak, she will show you another side of the picture, flashing up on a Powerpoint slide the words of different child’s father:

‘It is inconceivable in this day and age that, globally, there is no drug that can cure my daughter’


Any child diagnosed with cancer faces an uncertain future and to find out more about why this is so and what can be done about it, I went to visit Pam at the Clinical Trials Unit in Birmingham on a sweltering morning this June.

Pam and I have known each other for 5 years through involvement in various projects to do with childhood cancer, but I had never visited her on her ‘home turf’ and I was curious to know how the ‘nerve centre’ of childhood cancer research in Britain operates.

She welcomed me into a surprisingly modest office she shares with a sleek, carbon-frame Cannondale, the bike she uses for a 20 mile daily commute and the sportive challenge she promises she will get round to soon.

I start at the beginning and ask her what exactly the Clinical Trials Unit does.

‘Lots of people don’t know what a Trials Unit is and that includes many clinicians. There are about 30 Trials Units within universities in the UK, of which about a dozen or so are dedicated to cancer and 8 are core-funded by Cancer Research UK.

‘The aim of a Trials Unit is to be the place where an investigator comes with an idea about improving treatment, whether it’s giving radiotherapy in a different way, introducing a new drug, a new type of surgery, any clinical idea that changes the patient pathway. We work with them to see if it’s a viable idea and if it is, we help design the trial, collect the data – everything from concept to completion; the only thing we don’t do is recruit the patients.’

Who pays the piper?

I ask her who funds the research.

‘By far, the majority of paediatric cancer trials are charity funded. Cancer Research UK (CRUK) is our biggest funder; they fund the core team (at the Clinical Trials Unit) and if a trial is good enough, they’ll fund the trial too. We sometimes manage to get into collaborative partnerships with the pharmaceutical industry where they will give us a grant and a drug to support the trial.’

She gives the example of a major investigation into leukaemia.


Figure 1: 2008 Spend on Children’s Cancers (NCRI 2014)


‘ If you look at the AML trial which we’ve just launched, that has a lot of questions about how to use standard chemotherapy, but it’s also got a drug called mylotarg, which industry are still trying to get a licence for. The majority of the funding is from CRUK but there’s also a large grant from Pfizer – plus the drug. So that’s a true partnership, where you’ve got charitable funding delivering the academic questions plus Pharma contributing to answers we are interested in – important to patients, to families, but because they are also interesting to Pharma, they are investing money in it.’

She goes on to explain, though, that ‘we don’t necessarily need the industry’s involvement if, for example, we’re asking questions that are about generic drugs.’

When she refers to generic drugs, she means ones that are already commercially available. She explains that in past decades, many of the advances in children’s cancers were made by simply repurposing generic drugs originally licensed for use with adults. Even in the present day, a lot of research simply involves revisiting generics already well-established with children, refining their doses and tweaking their combinations. This process, however, she argues, has run its course.

Big Pharma and Small Biotechs

‘We’ve hit a plateau of improvement in many diseases,’ she explains. ‘To make the step changes we need in the future, I don’t think we are going to achieve that by just using generic drugs. We need new approaches, new drugs with different mechanisms of action that we can add to our armoury. That’s when we need the industry to give us access to their new drugs and innovations.’

The revolution in genetic science in recent years has stimulated a new wave of commercial drug development. These are the so-called novel agents that target illness at a molecular level and which hold great potential for shifting children’s cancers off the ‘plateau.’

Going ‘off-label’

A drug is usually licensed to treat a specific type of disease or cancer. If doctors feel that a particular drug may help a patient with a condition not included in the drug license they can prescribe that drug for the patient. But the doctor has to take full responsibility for the outcome. This is called ‘off label prescribing’. Many clinical trials for cancer use medicines ‘off label’ in this way. The trials want to find out whether drugs licensed for a particular type of cancer could help to treat other types of cancer.

The problem is that the pharmaceutical industry is adult-orientated. Its focus is on the blockbuster markets created by the common cancers that afflict older people, rather than on the messy patchwork of rare conditions that are children’s cancers. Pam’s concern is with the delays involved in waiting for new agents to be commercially developed for adults before we investigate their potential in children.

‘If there was a generic drug, a drug that had come off its licence now,’ she explains, ‘ and that was being used for adult cancer and we wanted to use it in children because we had scientific evidence that it could make a difference, we could go ahead and do that. 

‘But what we’re saying is, “Look, drug companies with your massive pipelines of new drugs, you’re developing targeted drugs that would be useful to children now not when that drug has been developed for adult illnesses.”

‘It’s about acceleration. We could wait until X or whatever targeted drug has been licensed for adults and then repurpose it for children and just carry on the way we have before. But we’re delaying access to children by sometimes 30 years. So the whole purpose of this is getting into the drugs pipeline really early, before the drugs are on licence in adults and let’s see if they’re interesting in children.’

I ask her why we are so dependent on the private sector.  Could not research centres in universities or hospitals simply develop the drugs themselves? The answer, of course, is about money.

‘It costs a huge amount of money and there’s high attrition rate [ in drug development] and academic departments would struggle to do that. I’m not saying they don’t exist. There are drug discovery units, for example at the Royal Marsden’s Institute for Cancer Research but they can’t turn on the high throughput screening in the way industry does. If an academic department developed a drug, there is no reason why we would not work with them, but at some point they will hand on the further clinical development to a small biotech and if it’s good, it will be bought up by Pharma. It’s the money that’s required to develop the drug.’

She gives an example from Birmingham.

‘My colleague, Frank Mussai, he’s doing some really interesting work looking at a particular pathway relevant to childhood cancers, and he’s found a biotech company based in Asia who produce the drug that targets this pathway. They’re not rich and they haven’t got the expertise to do the clinical trials, so they’ve been giving him small amounts of money to do his lab research. They’ve been giving him access to the drug to develop the laboratory research. Today we have finalised a grant application to the charity sector to do a trial in paediatric cancers .

‘Now if that drug were ever to become a blockbuster, then we would get some of that investment back so that we could develop the next set drugs. But that would be a rare event.’

From Brussels to Birmingham

The conversation inevitably shifts to the measure the European Union introduced to stimulate commercial interest in children’s drug development, the Paediatric Medicines Regulation. Both Pam and I are involved in campaigning to reform the Regulation and are aware of its disappointing record to date. However, she emphasises that it has had an effect.

‘I can remember the days, ‘she says, ‘of going to big cancer conferences and talking to a Pharma company at a stand about drug that was relevant to my research and they were really interested in talking to me as a medic until I said I was a paediatrician and they were like, “How quickly can I get this woman away from me?”

‘And that attitude has changed and it’s changed because of the Paediatric Regulation. There is a benefit; it might not have translated into new drugs for children but a positive attitude change has happened. ‘

I ask her about a similar campaign she was involved with, around another piece of Brussels legislation, the Clinical Trials Regulation.

‘It feels like it was a huge chunk of my life,’ she sighs. ‘But it was only two years’ serious campaigning  ’

The important point, though, was that the campaign was broadly successful and layers of unnecessary bureaucracy that hold trials back are scheduled to be peeled away.

What did you learn, I ask her, from the experience of that campaign?

‘That you had to work with the European Parliament and the relevant rapporteur,’ she says. ‘But rather late in the game we realised if you don’t have the European Council on board, the changes you want could be voted out. I think we were quite late in engaging with the member states. For the UK, we were in a better position because the MHRA (Medicines & Healthcare Products Regulatory Agency) were taking the role  on behalf of the Health Minister and they were sympathetic to the changes we wanted, so we were pushing at an open door. But that wasn’t the case across Europe. We met with health attaches from one of the member states and they were still concerned with clinical research in children being unethical. So they were miles away from where we wanted them to be and they were the people sitting around the table at the vote.

‘This is what we need to remember with the Paediatric Medicines Regulation. We know the arguments inside out but when you sit down with someone for the first time, they’ve only got this vague idea what you’re talking about so getting that sound bite, that message across is really important.

That’s what I learnt.’

Ethics and Equipoise

I pick up on the worries about the ethics of involving children in research   and ask her to explain about randomised trials.

Phase 1, 2 and 3 – What’s the difference?

Clinical trials are often divided into three stages or phases. Earlier phase 1 trials focus on how much of the drug it is safe to give and whether it actually shrinks the cancer. If a phase 1 is successful, the therapy will be tested more extensively in phase 2 and 3 trials. A new treatment usually needs to go through phase 3 before it is accepted as standard.

Phase 2 and 3 trials are often randomised. This means that people taking part in the trials are divided into different groups at random, with each group being given a different treatment or arm. Trials that compare three or more treatments are called multi-arm trials.


 ‘When you are doing a randomised trial, there should be no prior knowledge or belief that one arm is better than another. This is what we call equipoise. As a clinician, when I sit down with a family and I ask a child to participate, I can explain the background to both the arms but I should be able to say, hand on heart, I don’t know which one is better. If I did know, it would be unethical to ask someone to take part. ‘

She refers to the major randomised trial into Ewing’s Sarcoma, the illness my own daughter had.

‘It is like Euro Ewing’s 2012. Do you want to participate in a comparison of the known gold standard in Europe against the known gold standard in America? We cannot differentiate between the two and now we are asking the question which is more effective and which has fewer side effects.

‘Equipoise is about randomised trials. However, there is no equipoise at phase 1.

‘In a phase 1 trial, the ethical question is that you are asking a parent for their son or daughter to participate in a trial that may not have benefit for their child.

‘Now you can  ask an adult to take part in a phase 1 and it’s that adult’s informed decision on the basis of altruism and, undoubtedly, a little bit of hope that they’re going to get the “miracle response.”

‘The Declaration of Helsinki states, however, that you cannot do clinical research in children when there is not at least the potential for benefit, which means you cannot do the type of  ‘first in man’ studies you can in adults, starting from very low doses. There needs to be evidence from laboratory research or clinical trials in adults that suggests the treatment could have a benefit at the doses given to a child.

Talking to families

I ask her how she puts the option of a phase 1 trial to parents and child.

‘If I can give this in very personal terms , when I sit down with a family to talk about a phase 1 study, particularly a family I have never met before, the first thing I do is establish their understanding of where a child is in (I hate the expression ) the “cancer journey.”

‘So do they understand their child has no curative option? And that it’s effectively palliative at that stage? Because, without that understanding, the rest of the discussion about the phase I trial is almost dishonest. The eligibility criteria for most phase 1 studies is that there is no known better curative option. I then explain to them the background to the trial but I also say what the other options are and those might be purely supportive.

‘It might involve  using a drug like etoposide. We don’t have a lot of published data to prove this  has benefit but substantial clinical experience tells us that it has some success in holding back the progression of disease in some children.

‘I’ll explain where the trial is in terms of the drugs development, what the implications are of being in that particular trial. Does that mean more time in hospital, more blood tests, more investigations, backwards and forwards from half way across the country to visit me?

‘I outline all that.

‘I strongly dissuade families from going, “Where do sign?” ‘I always say, “Go away and think about it, talk about it.” And I talk to the child about it, depending on their age.

‘Morally, ethically and within the Declaration of Helsinki, you never ask a child to participate in a trial where there is no evidence of benefit. But the chance of the benefit has to be understood to be quite small and then it comes down to the motivation of the family and the child and whether they want, at least, to try something.

‘Now my experience is that each family is different. You get some families that respond saying, “I don’t really want to have anything more to do with hospitals – that means we can have some life together for a while.” They’ll do that. They won’t participate in phase 1 clinical trials – and that’s fine.

‘Then you get the different kind of family that says, “Whatever there is. They want to know if a phase 1 trial fails, what’s the one after that and what’s the one after that. They want to keep going. They want to be involved in something that brings their child to the hospital and might have the potential for a miraculous benefit.

‘There’s another kind of family. Often it’s done with the involvement of the child in the decision making; for example, slightly older children. They really know there isn’t much chance of benefit but they feel they want to be doing something, even if it is for someone else. That’s extraordinary, in my mind, but parents have said to me that at least we tried to do something even if that something is for somebody else.

‘I am forever in awe of all three sets of families. None of them is making a right or wrong decision. My job as a medic is to listen and answer questions and hope they go away feeling they have made the right decision for them and their child.

 ‘It’s a hard area and that’s why it shouldn’t be done in every centre in the country. It must be done by people who have that experience of talking to families about these issues.

‘Most of our experience is in breaking bad news to parents, because the majority of children treated are very young. It is harder to gain the experience of breaking this type of bad news to  the age group of children who are just starting to be old enough to understand.

I remember doing it for the first time when I was a junior doctor and I can remember, to this day, this teenager whose disease had become incurable quizzing me really hard about what was going to happen and I wanted to run away from the question’

‘It would have been really easy to say, “It’ll be fine” and patronise this teenager. But I stuck in there and that is something we all need to do.

In passing, I mention the difficult exchanges we had with our consultant over the only trial my daughter was offered in the whole period of her relapse. I relate the mobile call just before Christmas in which we turned down a phase 1 study of aurora kinase, a drug I have heard nothing of since in relation to Ewing’s.

‘That’s because the clinical development was abandoned,’ says Pam, ‘because it didn’t work. They completed the study but it wasn’t effective in anybody.’

Compassionate Use

We talk about the children who are never offered the option of a trial – because the trials are full, because the children do not meet the eligibility criteria or, as is more often the case, because the trials are simply not running.

I ask her about compassionate use, which allows patients access to new medicines, even hough they are not enrolled on a trial.

‘Compassionate use exists in America. We’ve got it here too. It’s called “Named Patient Access.”

‘As an example, it is possible for a child with leukaemia to get access to inotuzamab, even though there’s no trial open for that drug at the moment. We could open the trial of this drug when we get through all the regulatory paperwork. Compassionate use of drugs cannot substitute for proper drug development because we’ll never know if we just use it compassionately whether the drug should be properly developed and marketed and available to everybody.

I push her on whether we can get more children off phase 1 and onto phase 2 studies, where the emphasis is less on the safety of the drug and more on its efficacy. She talks about a new trial.

‘That’s the aim of E-smart. It will have multi-arms and, as new drugs become available and they’ve got their safety data, we can slot them into the trial. When the child has that molecular pathway identified, it doesn’t matter whether it’s Rhabdomyosarcoma or Ewing’s, does it have the target for that drug, can they enter the trial? And we’ll just keep that trial open and growing as long as we can get access to the drugs and that’s the sort of trial we need more of.’

Reference: NCRI (2014) Funding of children’s cancer research. Accessed 19 June 2016 at:

Article written by Chris Copland, Unite2Cure

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