Thinkwells an idea that came up with some of the patient groups that I work with. There’s a lot of ordinary members of the public out there who, who actually are interested in research and who would like to participate, like myself. You know, you never get invited by your doctor, and lots of questions out there about health, you know, Is it better to do, to really do a lot of exercise three days a week or a little bit every day? you know, and whod be interested and willing to participate. So the idea was we would set up a website where people could come together, and it’s, and it’s called The International Network for Knowledge about Wellbeing. So we’re concentrating on things that make you healthy, things people can do for themselves. And the idea is that the public come, they have their questions, we can look at the evidence and give it to them. We’ve also got a risk communication website so that people can have a look. If someone tells you Oh well, you know, there’s a one in 10,000 chance of, of dying from cervical cancer, and it reduces tenfold if you go, if you have screening, well, what does that mean? Is that a big risk? Is that a small risk? What other risks do we take like that? So there’s a database, you can compare it.

I prefer to give people information, but they need to be able to use that information sensibly. So this is part of what’s on the Thinkwell website, a risk communication website, so they can go and play with risks and if people tell them it’s a 0.006 risk, Well, what does that mean? Well, it will translate it back into, Well, that means that six, you know, in every 10,000 people might have it. So it translates it into more meaningful formats for people, and also enables them to get together and if they want to run a trial we’ll help them run a trial, and they can sign up to a trial. So one of the things we’re exploring for example is there’s – we don’t know, what we have in this country now, if you have a baby they have what’s called active management of labour, so there’s these things that they do to you, it’s all predetermined. Okay? And one of the things that they will do is the moment the baby’s born they clamp its cord. And there are people who argue that’s not a good thing. A third of the baby’s blood is in the placenta and cord and the argument is if you leave it a little bit, more blood will go back to the baby and it’s less likely to be anaemic. There’s an argument for delayed cord clamping but we don’t knows what’s right.

But health care professionals haven’t done this trial, but women would like to know. So our idea is that we’ll get women to randomise themselves on the internet, women who are having babies who are interested in the question will say, Yeah, I’m interested in participating in this research. I’m willing to be allocated by choice to choose delayed or early cord clamping. They’ll come on, we’ll say, Now toss the coin right, go and ask for delayed cord clamping in your birth plan. You go and ask for early cord clamping. And then we can compare the results because we’ll have two groups of – but it’s the women who are doing that trial, really, and we’re just taking their results with their permission to see if there is actually any difference in outcome.

I was certainly eligible and at that point I was intending to go into the trial, and just their inability to give me the most basic information – okay, maybe a research nurse is not, you know, the people running the trial might have known it and they – but you’d have thought you would have trained up the personnel at the frontline in that particular disease having, you know, I wouldn’t expect every nurse to know the kind of information I was asking, but I would have expected a research nurse on that particular trial to know it.

Was your worry more about what that meant for the trial and whether they’d actually done enough literature searching to make sure that this was a sensible intervention to choose? Or was it more about yourself and thinking Heck, I’ve got high blood sugar. I want to know that I’m getting a sensible interventio?

It was definitely about myself. It wasn’t thinking, Well, if they don’t know this then they’re doing the whole trial badly It wasn’t that thought. It was very much about my personal relationship with them, and thinking I, you know, I need this information. Why aren’t they giving me it And also, I don’t know whether it was true, but I wondered whether they didn’t want me to know, to know about it, because they didn’t want me, anybody doing anything that might affect the result of the trial. And I thought, That’s totally unethical And besides which, randomisation means there’s just as many irritating people like me that are going to go and do, you know, additional interventions in both arms so it doesn’t matter, you know. That’s the whole great thing about randomisation. You get two groups that are comparable, and yes, people go and do extra things but they do it in both arms so, so what? So I did get that kind of feeling about it, which I think, you know, given that there is something that you can do to prevent onset of diabetes, you know, get your weight down, do exercise, then if that was being withheld from me, rather than pure ignorance on behalf of the research nurse, then that’s totally inappropriate.

I did wonder if that was partly the motivation, that they didn’t want any confounding variables creeping in, and peoplehellip;.

Yeah, but you see they’re not really confounding variables; it’s just noise that means you need a bigger sample. Just like people filling in the wrong diary on the yoghurt trial – there’s bound to be odd, you know, I can’t remembe, and misclassification of the stool [laughs], you know, softer or harder than it was, you know? There’s bound to be that. The point is you’ve got enough people for the true result to be coming out despite that.

FOOTNOTE’ The number needed for each trial (the sample size’) is proposed by statisticians doing power calculations. In some cases a small number of participants may be enough, but if you are looking for fairly small changes in outcome you will need large numbers of participants to pick these up reliably.

Well, most trials, drug trials, are funded by the pharmaceutical industry, and I find that very worrying because they own the data then, and they can control the data. There was one rheumatoid arthritis drug called anakrina, for example, that we systematically reviewed, looked at the scientific evidence, and the drug company had suppressed some of the evidence. There were three trials that they used to get the drug licensed with about a thousand people in, which suggested it worked, and then after it was licensed for use there was a great big trial, bigger than the other three trials put together, a safety trial, in which they wouldn’t publish whether it worked or not, the efficacy data. In fact they claimed they hadn’t measured it, but we did have the protocol so we knew that wasn’t true. And it turned out, you know, they, they just suppressed that data. They claimed it hadn’t been measured. They said, Oh well, you couldn’t, this was a trial done in a different population. This was now done in a standard rheumatoid arthritis population instead of a highly selected population, and therefore it was too confounded to be usable But it was a randomised controlled trial, so the two groups were comparable. So my conclusion was that actually this didn’t work, if you use it in ordinary people, a drug that they were trying to promote for use in ordinary people. So yeah, the fact that trials are published by the pharmaceutical industry our defence has to be that the data is made public domain. But I, I think the government should be funding more trials. I think participation in research should be just built in to the health service, in such a way that it becomes very cheap and painless. You know, there’s not huge costs because part of the way we routinely collect data anyway.

What are the obstacles to that at the moment, do you think?

Research is not cheap. It costs. I mean, it isn’t cheap because it has to be done well. I think there’s absolutely no point doing research badly. I mean, I’ve seen people put together protocols and then cut down their sample size* calculations because it’s coming out at too costly. But I actually think what’s, you know, £2 million sounds like a lot of money, but if you’re preventing a lot of deaths it actually becomes quite trivial in terms of health costs. So no, I think it should be nationally funded, and I think it, more should be funded.

*FOOTNOTE’ The number needed for each trial (the sample size’) is proposed by statisticians doing power calculations. In some cases a small number of participants may be enough, but if you are looking for fairly small changes in outcome you will need large numbers of participants to pick these up reliably.

I think it’s desirable that people should know the results, I mean, that’s why we go into it. I personally feel worse, what’s worse, and is for a trial to come out and then not get published at all, you know, rather than the individuals being informed. And interestingly enough on the research ethics committee I’ve sat on and I’ve tried to bring up, They have no publication policy, they have no strategy for publishing this tria and being told that we’re not allowed to discuss that. Whereas I always think it ought to be built in that this data will be put into the public domain. I mean, I have a colleague who works in another country who was part of a multicentre trial for a major pharmaceutical company, and in the trial protocol it said results will be published within, I think it was 24 months of the close, after recruitment of the last patient. And they added into their, their centre, Should the results not have been published within 24 months of the closure of the trial, our centre reserves the right to publish the results for this centr, and they were excluded from the trial, because they insisted on that. They were told that could not be put in. Well, if they’re going to be published within 24 months, why could that not be put in? And so they refused to do the trial without that in. And they, and they – so that’s, that’s an insight. So who owns the data? I think the data ought to be owned by the people who are in the trial.

So I like the new strategies that are coming out, that data has to be put into the public domain and it should be a prerequisite, certainly for funding from government bodies. You know, if our government’s going to fund a trial, well, let’s have the results, and I – more than just the results, let’s have the data, suitably anonymised to protect patient confidentiality, in the public domain to be re-analysed, because even in the analysis there could be bias. So, I’m a great believer in transparency.

I actually think, what I’ve done – when I say I was a doctor, a public health doctor, actually for the last ten or twelve years, what I’ve done is learned how to look at research evidence and find out what it is we actually do know and put it together in a form people understand. So for example I put together systematic reviews of the evidence for NICE [National Institute for Health and Clinical Excellence]. For example we did some new drugs in rheumatoid arthritis, which were called anti-TNFs [tumour necrosis factor], things like etanercept. And to do that we needed to get the evidence for all the old drugs, and I was very shocked, having had rheumatoid arthritis for years and tried most of these drugs, to actually find that the evidence base for all of them was extremely poor. There was only one with really… good evidence, which was methotrexate, and it was the one drug that I’d actually refused to have, because the first patient I’d seen was a girl of 26 dying from side effects, and I’m thinking- and it just, the individual patient shocks you. So I had never wanted it, but actually it’s a very good drug, and having done the review for NICE, I actually switched my medication to methotrexate, and I’ve been a lot better than I’ve ever been before. So the evidence is important, and it’s that it influences me. No, so I think it’s quite shocking how the medical – people, the members of the public would be shocked at how many treatments we do that are not, have not been shown to be effective or indeed have been shown to be ineffective or, where we just don’t know. I mean, one that shocked me the other day was and in fact something I would like someone to do something about, what’s the first thing you do when someone’s had a heart attack and the ambulance turns up? Well, you give them oxygen, don’t you? Well, has a trial been done on it? Well, yes it has, and what does it show? Well, it wasn’t big enough to get a definitive result, but nearly three times as many people died in the oxygen group as in the other group, and yet we’ve never done the definitive trial because that could, almost, well it could be a chance finding. There are so few numbers of people dying it could so easily have occurred by chance. But with that evidence, if that’s the only evidence there is, why are we still doing it and why aren’t we doing the definitive trial?

Well, it sounds terrible that, you know, you’re just going to be chosen by lot whether you’re going to get the treatment or not. Well, I think the, the key thing is to explain to people, We don’t know which treatment’s better, so that whatever happens, we don’t know whether you’re going to be advantaged or disadvantaged by it I mean, there’s been a recent pro-biotic yoghurt trial in pancreatitis, and they had to actually stop it early because it appeared to be killing people. Now people probably wanted to get the pro-biotic yoghurt, but we didn’t know. And it’s, and it’s quite a shock to people that Actually, hang on a sec, these things could do more harm than good There’s some idea that if something’s natural that it can’t be harmful, but it’s just not true.

So I think people have to understand about that we don’t know. People have got to understand just how often we’ve been misled, and we’ve done things that really looked good and actually have turned out to do masses of harm, and that our only way is that as a collaborative venture, to go in these things together. I – how do I explain? When I’m teaching the public about trials, I don’t teach them about randomisation I, I say to them, you know, Here, let’s do, let’s do this experiment, you design i and then they design it in one way, and I say Can you think of why you might get a result which isn’t true due to the design, that is not an effect of the drug but for some other reason and they come up before, by the time we get to the end of the workshop, they’ve come up with randomisation as a method, they’ve come up with blinding, they’ve come up with all these things.

And because they’ve designed it themselves, because they see that unless you have two groups that are truly comparable, you can’t know whether if one group does better than the other group whether it was due to the intervention or due to some pre-existing difference. And then, you know, we play games with chocolate in envelopes and things and they note – to show that randomisation actually is strangely enough the best way of getting two groups that are comparable. it’s better than, it’s better than matching the groups. it’s strange but true. And if you play those games and then you realise that this is the best way to get two groups that are comparable, and if they’re not comparable, the whole trial you can’t believe the results, then people have no problem with it.

I think, you know, how much can you do, consent people? I think there needs to be a more generalised educational process really.

I’m actually a doctor and I work in public health, and I was working in [county] and I was in charge, I’d just been put in charge of the diabetes strategy there, and so it made me interested in the fact that nearby they were running a diabetes intervention trial, and it was for people who were well but who might be at high risk of diabetes, so people with a family history. So I decided to just go along because I thought Well, it would be interesting and I’d be interested in participating, I’m interested in research. And what happened in that trial is they, screening well members of the public, are looking for people who had high blood sugars but not, not diabetic levels, to see whether certain medications would prevent diabetes actually coming on, so people who were at high risk of developing diabetes. And what really surprised me was I actually turned out to have the high fasting blood sugar, so I – which made me eligible to go into the full trial itself. And I, I hadn’t anticipated that at all when I went into it. I was just sort of seeing what they did and you go along and you have your blood taken. And then they called me back and I had the high fasting blood sugar, which meant I was eligible for the trial. At that point they said Where there any questions? and so I started asking the research nurse whether there are other interventions like exercise and diet which could help, and she more or less said no, and she was very vague, wasn’t very sure, but she didn’t think there was otherwise they wouldn’t be doing this trial.

So I was rather upset at the lack of information that was forthcoming, having had a high fasting blood sugar, and so I decided to go off and look it up myself, and so I went on and found out that, you know, diet and exercise actually do – you know, there are other things you can do as well as taking medications. And so I was a little concerned that the level of staffing at the trial, that their staff were so poorly informed about this – which was fine, I was still going to go into the trial. And then a routine visit to my GP, you know, just to get a renewed prescription and he had in front of him a piece of paper telling him I had a high fasting blood sugar, and I was really annoyed because I had not been consented for my GP to be informed anything about this, and at that point I decided I would not go into the trial, because I just didn’t think it was ethical that they had breached my confidentiality in this way, so I just withdrew from the trial and didn’t do it.

Footnote’ The UK Clinical Research Collaboration points out that current ethical guidance is that if you agree to take part in a clinical trial, all your trial records and any information that is collected about you will be kept confidential, in the same way as your medical records. The researchers cannot tell anyone that you are in the trial without asking you first.

My main motivation for taking part is to help generate knowledge, which is why, I think, the results have to be into the public domain. All of them naturally concerned conditions I had – well, the azathioprine one was really, you know, I didn’t want to be poisoned [laughs] for something that was not going to do me any good. I’d like to know that it was doing me good. I find the health professionals, in a, in a disease that comes and goes, it’s an incredibly powerful illusion – you feel terrible you take something you feel better. And to join those two up in your mind – and if you look at all the crank remedies out there and all the alternative treatments, where there’s a lot of alternative treatments and herbal treatments, they’re all for diseases that come and go -eczema, rheumatoid arthritis – all these diseases that come and go naturally. And of course because people get what I thinks a powerful illusion of benefit just because they would have got better anyway, and I think it fools the medical profession too. People, I talk to colleagues and doctors. They have a much greater sense of how much good they’re doing than the evidence suggests is true, you know.

Yeah, so mostly less about personal benefit, but that arthritis one was much more personal motivation that you wanted to–

Yeah, that one was for me personally, although I do think N of 1 trials* could add to the sum total of knowledge, if done in a, in a co-ordinated way…But no, and I, and I think, I think it’s a, it’s a social contract. You just think of all the diseases out there. If every treatment was to be delivered as part of a trial against the next possible better treatment, we’d, our knowledge would advance tremendously. We’d all do, we’d all be so much better off from collaborating.

*Footnote’ An N of 1 trial is a clinical trial in which a single patient is the entire trial. Random allocation can be used to determine the order in which an experimental and a control intervention are given to the single patient. See Amanda’s other clips for more detail (Interview 22).

And then the last trial was very recently, which is, I have irritable bowel syndrome, not – it comes and goes, I mean, I can be perfectly normal for months, and then I can get attacks. And so there was a local researcher in the university I was working who was doing a trial of pro-biotic yoghurt versus plain yoghurt, not pro-biotic yoghurt, to see whether it controlled the symptoms of irritable bowel, and I was eligible and I signed up for it and it required you to drink, to eat two cartons of yoghurt a day for six months, I think it was, or – I can’t even remember. It was a long time, I remember feeling quite yoghurted-out by the end of it. And you’d just pick up your yoghurts in boxes with a number, you know, LR0911 on the top or whatever it was, and had to fill in a diary about how you felt. And I was interested in doing this trial because I’m interested, I’m actually interested – I’ve just switched jobs – I’m interested in the public running trials on themselves, you know. So people who like myself were interested in generating knowledge, we’d get together and we’d do it. And I just wanted to see how easy it was, and actually it’s, it’s quite difficult. You forget to fill in the diary and you think, Oh, what was it last Wednesday? or you scribble it on a piece of paper because you don’t have your book with you because you’ve gone away and, you know, you really don’t feel like a yoghurt but you have to eat it, and I was very compliant, I’m sure I was much more compliant than most people, just because there’s part of me that’s a bit of a researcher and so it makes you realise just how much noise or rubbish must be put into trials really because you’re thinking, you know, What was it? And then I’d think, Oh, well, I remember and then I’d find my bit of paper and it wasn’t true. Then I’d have to go back and change it, you know. So, but if I hadn’t found the piece of paper that misinformation would then have been put in. You had to, how many stools did you pass and what, how firm were they. There was a little chart where you had to categorise your, [laughs] your stool and this sort of thing. And actually during the whole period I was asymptomatic, and I was actually quite interested in how the research nurse dealt with me, because she, I think she was frustrated because there were no symptoms.

And also I was neither better nor worse and so the other half of her was wanting me to say I was better, when I didn’t necessarily feel I was better, I just felt I was unchanged. And I felt people were wanting a certain result, I really did get that impression, so I thought it’s, you know, it’s really important that staff are blinded as well. They can’t, you can’t help but want a result, that what nobody wanted to hear was, Well, I’m just the same. You know, I haven’t noticed any change at all, you know, so which is, was my situation. Later they told me that I had been on, on the pro-biotic yoghurt, which was a good thing because I was asymptomatic and I remained asymptomatic. So, who knows? Well, I say it was a good thing, but who knows whether that was, I haven’t seen the results of the trial yet, so.

Very difficult isn’t it? Particularly with those self-report kind of conditions–

Yeah,

–where there’s no sort of objective kind of, you know, like a tumour size shrinking is in a way easy to measure, isn’t it, but something like that?

I really think these things have to be blinded from staff as well, because you can’t help, I mean, if you’re running a trial, I want to run a trial, you can’t help wanting the result, because you, you wouldn’t be doing the trial unless you believed your intervention was effective, really, I think. Although they say you’re supposed to be in equipoise*. I don’t think you would ever begin a trial unless you actually believed there was good grounds to think that this will work.

* FOOTNOTE: ‘Equipoise’ means a situation where clinicians are uncertain which treatment is best literally it means they are balanced equally between them.

I’ve actually put together a protocol for a trial that we want to do on the internet that’s looking at selenium as a food supplement, as a tablet, for preventing cancer. Now the observational data is quite powerfully suggestive that it’s preventive of cancer, but we know from lots of studies that things that look good, like HRT for women and preventing breast cancer, when you actually did the trial they’re not. So I think researchers have to be sceptical, but you wouldn’t even start thinking about it unless there was some reason to think it was doing good.

I mean, I have actually shown my trial proposal to colleagues [laughs]. One colleague, whos a researcher in this building, actually turned round and said, Well, I’m going to take selenium. You know, until you get the results of this trial this is such powerful evidence But it could easily not be true. We need to do the trial.

Only I heard yesterday that we didn’t get funding for that either. And the evidence base is so powerful for that, I’m not quite sure why. They won’t tell you why, but we will pursue that one because it’s a really, really important trial.

So with that one you would have recruited through

The internet, we would have just got the people. We’d say, you know, Here’s a food supplement, you know, you’ve got a 50% chance of getting that or something that looks identical but which is inactive, a placebo, you know. Here’s, this is why we’re thinking of doing it, this is why we think it protects against cancer People would sign up, we’d either mail them the drug, the tablet, which is just like a vitamin tablet, or the placebo, and they’d take it. And the thing is it’s a very simple trial to do because we can just flag people for death or cancer in registries, in fact people don’t have to then do anything else. We’d like them to keep coming back on the internet and giving us information about their health, but if they don’t, if they never reappear again, we’ve still got their outcomes about whether they get cancer or die.

I think, well it, it depends on the disease and the illness etc. etc, you know, because there are some points in time when you’re just not capable of really thinking about anything else, you know, a cancer trial or something. You’ve just had the diagnosis, you’ve got other things on your mind, and then you just want to trust your doctor, I think. Well, I personally, in moments of my own severe illness, despite the fact I’m one of these people that loves lots of information and like to make my own decisions, I’ve often at that moment just thought I’ve got a doctor I trust. I’m not even thinking about this. You do what you thinks best and, you know, because I don’t want to think about it. I’ve got other things on my mind

I had been on gold injections for many years for my arthritis and, you know, if I got iller they put the dose up and then as I got better they would lower the dose and, and I was just thinking, Well, you know, this is crazy. Of course I’m going to get better. If I’m ill I’m going to get better, because it’s a disease that cycles. And I had asked them – this was long before I was a doctor – if they would just give me water sometimes instead of gold and not tell me about it, at which they laughed and said Oh no, we can’t do that.

Later on I was told I was being withdrawn from the gold, because I had beginnings of kidney damage and, you know, they would try something else, azathioprine, which is quite a toxic drug. So this time I asked if it could be introduced experimentally without me, you know, being told what the drug was, because they said the gold had probably not been doing me much good even though I’d had it for years and years and years. So it’s known as an ‘n of 1′ trial – a one person trial where you have the drug, then you have something that looks like the drug that isn’t the drug, and you don’t know when it’s starting and ending, to see whether actually it is related to your symptoms, because in a disease like rheumatoid arthritis you can be very ill and then you can be better just because the natural variability of the disease.

And my rheumatologist, she was very keen to do it with me and we looked up how these trials were done. We found a pharmacist who is experienced in n of 1 trials, we got the drugs from the [laughs] pharmaceutical industry, and we were going to do the trial. But then, interestingly enough – which was simply giving me the drug – we were then told we couldn’t do it because it would have to go to an ethics committee because it was an experiment, which I found ridiculous. You know, you can give me the drug, you don’t know whether it’s doing me any good, it’s toxic, but to give me it in a way that I could actually find out whether it’s doing me good suddenly we weren’t allowed to do it. And the other thing that was very interesting about that trial was the placebo was different from the drug, so you could tell which was which. And we contacted the pharmaceutical company concerned and they said yes, it was always like that, and it was like that in the trial, which made me very suspicious now about blinding in trials. You just think, God. I could distinguish those. So then we had to look up things like, we were going to crush them or put them in capsules, but because it’s toxic, that breached health & safety regulations. Then we were thinking about covering [laughs] them in chocolate. But by the time we’d done this I was getting very ill. My consultant just started me on the drugs, she said, We just can’t wait to set this up, and it didn’t work. I actually got to quite a toxic dose. She said This is clearly not working We were upping the dose and then we just stopped it, so we never got through the process of doing the trial, because it was blocked by the powers that be saying it needed to go to an ethics committee, and that was just taking way too long for me as an individual patient.

Were you trying to go through the ethical process?

Yeah, we, at that stage we were going to go through the ethical process, we’d drawn up a protocol, we had everything written and we were still exploring methods of making the drug truly blinded so I wouldn’t know what I was on and that – so we, we hadn’t actually submitted it to an ethics committee because we were still, hadn’t we’d just got to the chocolate-coatedtablet idea when, by which time [laughs] we she’d decided it was toxic and was not going to do any good anyway.

So then I stopped that.