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Clinical trials, Yellow cards, Chemo brain, Conduct Disorder

Dr Mark Porter puts the pharmaceutical industry in the spotlight after clinical trials are criticised, and looks at if childhood adversity leads to structural changes in the brain.

Dr Mark Porter puts the Pharmaceutical Industry in the spotlight as some clinical trials are criticised for testing new drugs against a weaker rival so that the results appear much better than they really are. Kamran Abbasi takes on Dr Bina Rawal from the Association of British Pharmaceutical Industry to discuss if the hurdles are being set too low, so that a new therapy comes out on top.

And what if sustained periods of adversity in childhood are associated with permanent structural changes in brain development? So suggests new research into adolescents with Conduct Disorder - a controversial diagnosis given to 1 in 20 teenagers in the UK with aggressive or anti-social behaviour. Many of these children will have been exposed to severe abuse, but do these findings have implications for common family discord that lasts months or years? Mark Porter investigates.

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28 minutes

Programme Transcript - Inside Health

Downloaded from www.bbc.co.uk/radio4

 

THE ATTACHED TRANSCRIPT WAS TYPED FROM A RECORDING AND NOT COPIED FROM AN ORIGINAL SCRIPT.  BECAUSE OF THE RISK OF MISHEARING AND THE DIFFICULTY IN SOME CASES OF IDENTIFYING INDIVIDUAL SPEAKERS, THE BBC CANNOT VOUCH FOR ITS COMPLETE ACCURACY.

 

 

INSIDE HEALTH

 

TX:  26.02.13  2100-2130

 

PRESENTER:  MARK PORTER

 

PRODUCER:  ERIKA WRIGHT

 

 

Porter

Hello. Coming up today:  How your upbringing might determine your future.  We examine the implications of new research suggesting that sustained periods of adversity in childhood are associated with permanent changes in brain structure and function - something that is bound to worry any family struggling to deal with challenges like abuse, deprivation or marital discord. 

 

Clip

I couldn't understand why I'd become the person I had or why I felt like I needed to deal with that the way I did.

 

Porter

But is it cause or effect? We will find out what the experts think later on.

 

First drug trials.  The pharmaceutical industry has been criticised recently for burying research that fails to show their products in a good light, but now there is growing concern that some trials are being conducted in a way that is likely to make a new drug look to be more of an advance than it really is. Using a simple analogy - if I wanted to make myself appear to be a good runner, I am unlikely to take on Usain Bolt - because I would look a lot a quicker up against Fatty R Buckle.  And that is essentially what trial organisers are being accused of?  Inside Health's Dr Kamran Abbasi has been investigating.

 

Abbasi

Yes it's an issue that's been bubbling under for quite a number of years and it's increasingly coming to the fore.  And if I give you one particular example:  A study that was published very recently, only last year, looked at research that was done into new treatments for rheumatoid arthritis and of 63 trials that the researchers evaluated they found that 54 were using either a placebo or a treatment that was ineffective, that shouldn't have been used as a control in those trials.  So what that ended up doing was about 9,000 out of 13,000 patients were receiving treatments in the control arms that they shouldn't have.

 

Porter

So the implications are two fold as I see it, one is that the patients who are entering the trials themselves they're not getting gold standard treatment, they might be getting a second rate treatment in the trial, so they might be missing out.  But in terms of larger numbers that that product may then get approval and be released into the general market and it's not actually as good as it appears to be because it's being compared against a weaker rival

 

Abbasi

Yes they're precisely the issues and the concern is - as you said - this is being done deliberately to promote a particular drug or therapy.

 

Porter

Bina Rawal, the research medical innovator director at the ABPI, Bina, that's quite an accusation, what are your thoughts on that?

 

Rawal

Well allow me to take this opportunity to explain the process which is actually a very complex process to develop a new medicine.  At the very outset a clinical trial study is not designed by a company in isolation, so the company will be talking widely to the clinical experts in the disease area, they were consult the prevailing clinical guidelines and they will also consult the regulator.  And besides the regulatory guidelines they will also have to comply with ethical guidelines.  So in terms of designing a trial the study then - apart from being approved by the regulator - has to pass an independent ethics committee.

 

Porter

But Bina I'm not picking holes in the way the trials are designed, what I'm saying is that actually however they're designed and whoever's fault it is - whether it be the clinicians, the drug companies, whatever - that actually this is happening, that the hurdles are being set too low.  Do you see that as a problem?

 

Rawal

Let me take the example cited by Kamran just now.  The clinical studies done to develop new drugs against rheumatoid arthritis.  The studies would have been within the prevailing clinical guidelines and every single one of those studies would have been cleared by an independent ethics committee as being ethical.

 

Porter

But that's not the issue though, the concern is - and this is something that's been rumbling for a while - that actually the comparators are too weak, that the drugs we're using to compare - whatever the guidelines - the guidelines might need changing - do you not think that's an issue?

 

Rawal

If the comparator is too weak in your words the studies should not be approved by the ethics committee or the regulator and the clinicians would not be entering subjects into a trial that was going to be harmful to their patients.  And I can assure you that at the time the trials are designed they will be seeking out what the prevailing best available gold standard treatments are to compare their medicine with, because after all the company wishes to replace that gold standard with their new medication.

 

Porter

Kamran, the guidelines have been in place, they are there to ensure this is not happening but you're saying it is happening, despite those guidelines?

 

Abbasi

Well it is happening and - well first of all I'd say Bina is correct in saying that it's not simply the pharmaceutical companies that are responsible, we're not saying that but where you are wrong is to say that just because you're conforming with clinical guidelines that's sufficient, that's where the problem lies.  The problem lies in taking responsibility for what's happening and one of the fundamental issues - you say there's lots of research done prior to a trial being started but in fact there is evidence that what we call systematic reviews, the review of the literature to establish what the best comparative drug is, these aren't being done prior to trials starting and they should be mandatory prior to trials starting.  And if the pharmaceutical industry is a responsible funder, supporter and sponsor of trials you should be pushing for that rather than saying that because an ethics committee's approved it, because clinicians are working on the trial then that's okay, that isn't sufficient.

 

Porter

Bina, as far as you're concerned or as far as the ABPI is concerned there isn't a problem at the moment, you're happy that new drugs coming on to the market are being compared against the best that's out there at the moment?

 

Rawal

I'm saying that what we have is an extremely rigorous scientific approach, a very highly regulated industry...

 

Porter

Does it work though?

 

Rawal

I think we have had tremendous advances in the last few decades, the mortality from conditions such as HIV AIDS has fallen by 80% or more on account of the way the industry been able to work collaboratively with clinicians, with regulators, with patients to develop these new medications.

 

Abbasi

I'm afraid those statements just aren't supported by the evidence.  I mean I've mentioned rheumatoid arthritis, I can mention any number of conditions in which inappropriate comparison drugs are being used in trials, have been used in trials and there is a wealth of evidence that unfortunately some of these trials, many of them, are constructed to show the drug in its best light, shall we say, rather than do what's best for patients and there's much evidence that shows that patients end up being harmed and receiving sub-optimal treatment as a result.  So I'm afraid although you may think that's the case the reality of the evidence doesn't support that.  So if that's the case surely we need to change the process, we need to re-engineer the way we design and conduct clinical trials...

 

Rawal

The process is continuously being re-engineered.  The drug development process has changed dramatically in the 20 years I've been involved with the industry.  We're in a process of continuous improvement and continuous change and wherever these sorts of issues are raised we work assiduously with regulators, with healthcare professionals, with the patient support groups to improve processes.

 

Porter

Kamran, do you think the concerns are being listened to?

 

Abbasi

Well no, I mean systematic reviews have been around for many, many years, they're not new, we're not talking about systematic reviews here and the evolution of systematic reviews, what we're talking about is that we're talking about the evolution of clinical trials so the primary concern is the patient, the best interests of the patient, we need to make sure the trials are justified, that the right comparators are being used.  And if I could wake up one day and think that companies and other funders and sponsors were more concerned about patient value, rather than shareholder value, I'd think we'd probably got somewhere.

 

Rawal

In the end there's no point developing a drug that doesn't serve the patients' needs.

 

Abbasi

And the industry always says that, it's a standard industry response that it's looking after the welfare of patients, the medicines are for the benefit of patients but again I will say to you the evidence - and if we look at this particular issue we've been talking about, you say things evolve, but there's research published almost every year to demonstrate that it remains a problem, nothing really has changed.  And unfortunately you can think about the benefit of patients but ultimately what's happening is there are many therapies that are being trialled, tested, marketed and sold that are sub-optimal and some that are frankly harmful.  So I think industry has to take responsibility because industry sponsors say 90% of clinical trials that take place, so there's a responsibility...

 

Porter

But doctors run them.

 

Abbasi

Yes it's a responsibility, it's a multi-factorial issue, so there's industry's responsibility, it's ethics committees that are approving trials without systematic reviews, without the right comparative.... and it's clinicians who are being involved and not properly scrutinising the evidence and also thinking for the best of patients.

 

Porter

We must leave it there - Dr Kamran Abbasi and Dr Bina Rawal thank you very much. If you would like to explore this issue more, you will find a useful link on our website - go to bbc.co.uk/health and click on I for Inside Health.

 

Time now for some of your feedback, and continuing the medicines theme our report on the falling numbers of Yellow Cards submitted by healthcare professionals and the public to report drug side effects, prompted a number of you to get in touch.

 

Helen e-mailed to say:

 

Helen (read)

It's not surprise to me that the yellow card system is failing.  A couple of years ago I had a reaction to a drug and asked my GP to fill in a yellow card and he refused to either fill one in himself or give me one to fill in.  If all GPs are doing this then it's no wonder it isn't working.

 

Porter

And Patrick contacted us to say that he had never been offered a Yellow Card by his GP or pharmacist despite suffering troublesome side effects from a number of medicines.

 

Well Patrick, you won't be offered one unless you ask - but you can't ask if you don't know about the Yellow Card system - a catch-22 that no doubt partly accounts for the low numbers sent in.

 

You can get one from your GP or pharmacist, but probably the simplest way is to use the online version - and there is a link to the relevant website on our page of bbc.co.uk/radio4. Or simply Google Yellow Card.

 

Our report on chemo-brain seemed to strike a chord too.  Paul e-mailed to say:

 

Paul (read)

My wife had chemotherapy for breast cancer in 2008.  She was given a leaflet which mentioned possible memory problems as a side effect.  A few months after successful treatment she had memory losses which worsened.  Although her NHS specialist sympathised and gave this the name "chemo-brain" she was unable to do more.  After weeks of intensive internet research I discovered that chemo-brain is well known in the USA.  In the end we saw a doctor in Maine who assessed her and offered cognitive therapy and agreed to work with a UK counterpart.  This was adapted to CBT here and she learned strategies to cope with memory loss.  These help her even now when her memory fails.  Chemotherapy's prevalence suggests its side effects need more care and attention than a line in a leaflet.

 

Porter

And the symptoms we described were all too familiar to Keith who had chemotherapy for bowel cancer.

 

Keith

My concentration span was deteriorating rapidly during and after treatment and I gave up trying to read when I realised I couldn't recall anything that I had read.  Though an avid letter writer I found it impossible to compose a letter.  One of the contributors to your programme did suggest that recovery could take months or even years, however, I regained both concentration and attention span within weeks of my operation and now, as my wife would substantiate, I am back reading books and newspapers, no problem.

 

Porter

And a PhD researcher from Manchester got in touch to say that she's currently working on chemo-brain at the moment.  So research is on-going.

 

And if you want to share your thoughts, or ask us to look into a health issue that is confusing you, you can e-mail insidehealth@bbc.co.uk or send a tweet to @bbcradio4 including the hashtag insidehealth.

 

Now some new research that got us thinking here at Inside Health - a study demonstrating that the brains of teenage girls with behavioural disorders look different to those of their peers. The researchers scanned the brains of girls with conduct disorder - which is associated with aggressive and anti-social behaviour and thought to affect as many as one in 20 teenagers in the UK - but the findings could have implications for other children too. Not least because of the possibility that the structural differences in the brains result directly from the environment that they have grown up in. Could something about their upbringing have permanently altered the way they think and react?

 

The idea is controversial, but so is conduct disorder.  Ian Goodyear is Professor of Child and Adolescent Psychiatry at the University of Cambridge.

 

Goodyer

Conduct disorder is a descriptive diagnosis involving a range of anti-social behaviours - lying, stealing, destructiveness of property - and these tend to be persistent features that last at least 12 months and are found often over many different environments - the home, the school....

 

Teenager

I guess you could say I didn't have a normal upbringing, it wasn't exactly your standard nuclear family set up. 

 

Batmanghelidjh

My name is Camila Batmanghelidjh, I am a psychotherapist and a founder of a children's charity called Kids Company.

 

Porter

What does conduct disorder mean to you?

 

Batmanghelidjh

I don't actually like the term but what the children describe is they get some sort of attention build up, that they describe both at brain level, i.e. they experience it in their heads but also in their body, it's almost like they're building up to be a bomb.

 

Teenager

I felt like there was something inherently wrong with me......

 

Batmanghelidjh

And they can't calm themselves down, so what they do is look for a situation where they can expel this tension and it's usually in either finding someone to attack or to harm or it's damaging property but it's got to be something that's significant enough to get rid of the stress that they're experiencing.  And after they behave badly there's a dual consequence, one is that they feel slightly relieved because they've got rid of the tension but then they've got to deal with the rage of the people around them who are now angry with them for having behaved so badly.

 

Bowman

Conduct disorder describes a very particular manifestation of behaviours that most parents will have experienced in their own children at some point.

 

Porter

Deborah Bowman is Professor of Bioethics, Clinical Ethics and Medical Law at St George's University of London.

 

Bowman

It is a term with reservations and I guess those reservations are as long as we're open about the fact that it's a value laden diagnosis, as long as we understand that it's an uncertain diagnosis and I think embedded within it are all sorts of ideas about what a good child is, what a naughty child is, what's acceptable, what isn't - how many times does a child have to steal a penny before he or she becomes a thief, those sorts of ideas.  And I think the term diagnosis might be problematic in itself, it does suggest something, at least to me and maybe I'm unusual in this, but something certain that might go in notes that will be shared, that will become shorthand.

 

Batmanghelidjh

Any kind of descriptions around these children is always negative, so people describe them as evil, as selfish and what actually people don't realise is these are children who are really struggling to participate in society in a pro-social way but they just can't manage it.

 

Porter

And what sort of backgrounds are these children coming from?

 

Batmanghelidjh

I haven't seen a child come with emotional and behavioural difficulties for no good reason and that's why I don't like these labels because when people call these children conduct disordered children they're putting the blame almost on the child, as if the child carries the dysfunction.  Whereas actually these children in many ways are generated as a result of poor conditions of care provided by the adults around them.  Often they are violated, they can be sexually and physically abused, they are neglected and they're just children who sometimes have had parents with addiction problems, very poor boundaries, very poor consistency - the whole infrastructure of care around them is usually poor.

 

Fairchild

It's estimated that between 3-5% of school age children will meet criteria for conduct disorder.

 

Porter

Dr Graeme Fairchild is Lecturer in Psychology at the University of Southampton.

 

Fairchild

Generally in the UK most people are not given a diagnosis, it's not a condition that is treated often by doctors or psychiatrists.  I can understand people being wary about medicalising this kind of problem, it's a controversial diagnosis but what we're doing at the moment is not very effective, particularly in the persistent end - the reoffending rates for young offenders who are put into custody then come out are around 80 or 90%.

 

Porter

And if you were to look at prisoners for instance, I mean what proportion of them might have had the condition as children do we think?

 

Fairchild

Nearly all of them, I would say at least 80-90% of them.

 

Porter

Dr Fairchild worked with Professor Goodyer on the research showing that the brains of teenagers with conduct disorder look different to their peers.

 

Fairchild

We did several different studies looking at both the structure of the brain and the function of the brain.  The structural studies showed that an area of the brain called the amygdala was smaller in volume.  This is a part of the brain that's involved in reading emotions, perceiving emotions, also feeling emotions yourself - so strong emotions of fear - people who have damage to that part of the brain show a range of problems in perceiving emotions and feeling emotions themselves.  That was the first study that we did on boys.  In the second study that we did on girls more recently we found relatively similar findings - the amygdala was smaller but also an area involved in empathy, the anterior insular, was reduced in volume on both sides of the brain.

 

Porter

Is this cause or effect and how do you differentiate between the two?

 

Fairchild

It's very difficult to say what the causal direction is, we know the adversity - at least severe adversity - can affect the brain, how does it do that?  Probably partly due to actions on the stress system which certain parts of the brain are more vulnerable to stress hormones that might be produced in large amounts if you're abused early in life.

 

Porter

So actually whatever these external factors are having a direct function on - the brain's plastic at this stage isn't it in what we're saying?

 

Fairchild

It's plastic even in adults.  If I was to teach you a new skill you might be able to see changes, structurally or functionally in your brain, as a result of you learning a new skill.  But in childhood, infancy, teenage years the brain's probably more plastic.

 

Batmanghelidjh

I've been saying for some 10 years that these children's brains are different.  What's amazing about this brain research is this notion of neuro-plasticity, that your brain is continuously being structured and developing as a result of the care conditions that you're exposed to meeting your genetic potential.

 

Goodyer

It is clear that brain growth is susceptible to environmental influence.

 

Porter

Professor Ian Goodyer.

 

Goodyer

And therefore it's reasonable to hypothesise that the early rearing environment is likely to have effects on the efficiency and the effectiveness of brain growth and it might particularly be true for systems that are involved in the psychological aspects of existence rather than say the fundamentals of eating and drinking and sleeping.  So what would happen if we started to study common family adversities - parental discord, family arguments, disharmony with your offspring and chronic disharmony with your partner - that occurred for more than six months and to which children were exposed to within the family atmosphere, these are relatively common features.  And when you do that you start to see that there may well be effects on brain and mind that are not simply going to be seen in the very severely assaulted child but may well occur in the child or the adolescent who's been exposed to this kind of chronic family discord that is likely to result in sub-optimal parenting and poor family environment.  Studies on those kinds of young people are uncommon at the moment.  Well we've carried out a study such as that I've just described, as have some colleagues in Holland and one or two others, and we are beginning to see from these studies that unfortunately a sub-optimal family environment probably over months and years, rather than days or weeks, may well have effects on brain development and functions, particularly social functions such as your ability to relate to others and your ability to make decisions about other people's intentions towards you in later life.  Now this is very, very new.

 

Batmanghelidjh

I believe there are children who have less resilience or they may have a propensity to presenting with disturbances if their environments are disturbing.  So I think there is a sensitivity that can get triggered by adverse environmental conditions but I am absolutely certain that the key ingredient, the switch if you like, is adverse care environments.  One of the most moving experiences I've had is actually drawing for children, who have had a history of behavioural and emotional difficulties, a picture of the brain and explaining this whole notion that you use the front part of your brain, your pre-frontal cortex, to regulate and calm down the emotionally driven centres of your brain - your limbic system - and explaining how this disregulated state happens and often the experience with children is they burst into tears because for the first time they feel someone actually understands what's happening to them and someone's stopped calling them bad and is actually meeting them where they're at.  And our experience shows that once children have this information they do begin to exercise more responsibility - I've seen kids really improve.  The capacity for violence doesn't disappear in them but whereas they would use that violence every five minutes in some kind of disruptive behaviour you begin not to see it unless they're absolutely exceptionally stressed.

 

Teenager

It was such a relief to have someone sit down and explain very clearly that I wasn't a bad person, that the way that I felt and the way I communicate that with the world was a direct result of my past experiences and not because there was something wrong with me.

 

Porter

So what else can be done to help teenagers with conduct disorder, given that it impossible to turn the clock back and change their upbringing? Graeme Fairchild:

 

Fairchild

Well first of all a lot of them don't get any help whatsoever, they have to commit a crime, usually quite a serious crime to get help.  Child and adolescent mental health services often don't treat them, they may even have it as an exclusion criterion, so...

 

Porter

Because they're so difficult to manage.

 

Fairchild

Because they're difficult to manage, because they don't turn up to their appointments, because their families might not be involved.  So it does have a very significant impact on society, partly because it's a controversial condition and partly because we don't have very many effective treatments psychiatrists don't tend to treat the condition, there are no effective drug therapies but the latest thinking is that you can't just help the individual, you have to help the systems around them, so you have to help their family structure, for example their parents might have mental health problems that you need to treat as well, you need to get them to associate with different peers who have not engaged in criminal behaviour, to get them back into education - often they're out of school or college - or get them a job.  So you need to work on multiple areas of their life to help them.

 

Porter

And is there evidence already that those sorts of interventions can have a significant impact?

 

Fairchild

There is, so what I'm referring to is called multi-systemic therapy, it was developed in America, it's being trialled at the moment at multiple sites across the UK and there is evidence that it will be effective, however, it's an incredibly expensive therapy - it's in the tens of thousands of pounds per year for each individual.  So only the very severe people get it, only the people who are at a high risk of going to jail or getting thrown out of their homes and getting taken into care get help. And so I think that that's the wrong way round - we shouldn't be dealing with it in a crisis way, we should be helping these kids before they get to the stage where they're almost going to jail or they will go to jail.

 

Batmanghelidjh

The mistake that we're making actually in relation to these children is that we are using a moral framework to intervene with them, we're believing that if you punish them and you apply sanctions and rewards that they will improve.  That works for a child who has an organised brain and has memory capacity to hold on to the idea of a punishment - what it felt like and enough calm to recall that memory before they're about to do something bad.  But what happens with children with disturbed emotional states is their memory's not organised, they often don't remember mild punishments, they only remember extreme risk and consequently the moral corrective framework doesn't work with them.  So what you have to do is you have to partner with these children, explain to them that their brains have changed as a result of the difficulties they've had - and this is very important because you're getting the child to take greater responsibility for their difficulty, you're now not saying to them you're badly behaved morally flawed little boy or girl, you're saying you have a challenge in managing your own emotion and your own energy because of the things that have happened to you and we together need to help you find better ways of handling this situation.

 

Porter

Camila Batmanghelidjh.

 

One interesting development of the discovery of structural brain differences in conduct disorder is that scans are now being submitted by defence lawyers to mitigate serious crimes in the States - it is not all their fault , they have a problem with their brain which mean they are prone to impulsive violent behaviour. And the courts are listening.  There is a link to Ian Goodyer's and Graeme Fairchild's research on our website - bbc.co.uk/radio4 and head for Inside Health

 

Next week I will be finding out why it is so important for people with epilepsy to plan ahead if they want to start a family - or add to an existing one - and why getting your contraception right is the vital first step in the process. Join me then to find out why?

 

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