The PACE Trial – particularly the huge reaction to it – was the subject of lengthy interviews on Australian national radio channel ABC's ‘Health Report' on 18 April 2011. Norman Swan separately interviewed one of the principal investigators Professor Michael Sharpe and the editor-in-chief of The Lancet, Dr Richard Horton – whose journal has this week refused to publish a number of letters of criticism of the trial (including one from the ME Association).
Listen HERE to the debate or read the ABC transcript below.
Transcript
This transcript was typed from a recording of the program. The ABC cannot guarantee its complete accuracy because of the possibility of mishearing and occasional difficulty in identifying speakers.
Norman Swan: Good morning and welcome to the Health Report. This week, an enormous row over chronic fatigue syndrome, it's about a paper in The Lancet published last month has generated an almost unprecedented reaction from some people claiming to represent patients with the condition. Some see it as a clash between ideology and science over fundamental differences in how chronic fatigue syndrome is conceived in people's minds as an incurable hopeless condition to which one adapts as best one can, or as a condition from which at least some recovery is possible for some people.
In a moment you'll her from the Editor in Chief of The Lancet on this extraordinary response to the paper. But here's one of the researchers who conducted what's called the PACE trial, which actually despite the trench warfare has good news for people living with this syndrome.
Michael Sharpe is Professor of Psychological Medicine at the University of Edinburgh.
Michael Sharpe: Chronic fatigue syndrome refers to a condition where people suffer from chronic and we usually mean by that at least 6 months, fatigue which has a very substantial effect on what they can do. So a condition which affects people's ability to do day to day activities although there are a lot of different definitions and that's the route of some of the controversy.
Norman Swan: This trial that you've just reported on in The Lancet sounds like an enormous exercise.
Michael Sharpe: Yes, well we set out some ten years ago to try and address the question of the treatments for which there is some evidence which have been advocated. What was the relative effectiveness of these treatments for people with chronic fatigue syndrome? Importantly, because there was concern about this, do any of the treatments do harm? So to answer this question we set up with funding from the Medical Research Council in the UK, a large UK wide trial which recruited 640 patients to try and provide definitive answers to these questions. And there has been research done before on this but it tends to have been small studies. So we really did our best with a ten year 640 patient multi-million pound study to provide clear answers.
Norman Swan: Now just go through these treatments because some of the advocacy groups for people with chronic fatigue favour some kind of treatment over another.
Michael Sharpe: Yes, well this was the part of the controversy that we set out to address. The treatments for which there was some evidence were cognitive behavioural treatments, which is basically a talking treatment which aims to help people be able to gradually increase activity by addressing concerns they have about doing that. The second treatment is called graded exercise therapy which again tries to help people working with them to gradually increase their activity but does it very much in an exercise treatment based way.
Then there was another treatment for which there really wasn't much evidence but a lot of support which was called pacing and we evaluated in this trial the adaptive pacing therapy. And that has a different philosophy which is helping the patient to manage whatever energy they have in the most effective way and if they find they are able to do more that's terrific, but not to really push them or encourage them to try and up the amount they're able to do.
The other treatment of course that most patients probably get is seeing a hospital doctor with an interest in the condition. Those were the four treatments that we trialled. Everybody in the trial got to see a specialist doctor as well as that one group got the cognitive behaviour therapy, one the graded exercise therapy and one this pacing therapy called adaptive pacing therapy.
So the controversy really underlined that bit, ‘are you best in this condition to work at trying to rehabilitate to do more or are you best to adapt as best you can to the condition and allow healing to take place'?
Norman Swan: And the advocacy groups felt that there was some danger in graded exercise or cognitive behavioural therapy.
Michael Sharpe: You're absolutely right and that's why we looked very hard in this trial for evidence of harm because there was concern based on anecdotal reports and surveys of members of patient organisations that if you undertook the more rehabilitative treatments you could actually end up making yourself much worse.
Norman Swan: And to what extent did you engage the patients groups in this design and planning of this study?
Michael Sharpe: Way back when this trial was planned we did this in partnership with one of the major UK patients organisations, which is called Action for ME.
Norman Swan: ME standing for myalgic encephalomyelitis.
Michael Sharpe: Yes, that's right and they were able to comment on and advise on the trial materials. Also during the process these trials involved an awful lot of oversight and regulation and there was a patient member of the committees going all the way through the trials.
Norman Swan: And did Action for ME stay with you for the whole time in support?
Michael Sharpe: Action for ME stayed with us for the whole time right through to the end of the trial.
Norman Swan: So what did you find?
Michael Sharpe: Two of the treatments did very much better than two of the other treatments. So to put that another way the treatments fell neatly into two groups – graded exercise and CBT having a better effect on fatigue and physical functioning than pacing and medical care. We were surprised how little benefit pacing added to just seeing a doctor. The finding in terms of harm was that there was a very low rate of deterioration or harms in the trial and this was very similar across all the treatments.
When people say that they got worse with the treatment it's difficult to disentangle that from fluctuation in the ailment. But because it was the same across the treatments it would suggest that none of these treatments are harmful.
Norman Swan: And how long did they have the treatment for, I mean how long did the graded exercise go on and the CBT and so on?
Michael Sharpe: It was about 12 sessions of treatment in the first few months of the year and then the outcome measured at the end of the year.
Norman Swan: One to one or group therapy?
Michael Sharpe: It's important to say that these treatments were given very carefully on an individual basis with manuals and were tailored to each individual patient on a one to one basis. And I think one of the differences perhaps between the trial findings and the anecdotal reports is that I think out there people give these treatments in a variety of ways, maybe not a very good way. So I think it's very important when considering results of this trial to remember that this is a fairly intensive, individual treatment following a manual very carefully and tailoring it to the patient.
So then the next question is how much better did you do and we set a threshold for what was a clinically meaningful improvement. About 6 out of 10 of the people who had CBT or GET made a clinically meaningful improvement compared with about 4 out of 10 people who had the pacing and medical care. So the differences we're looking at here are clinically useful but they're not actually enormous.
Norman Swan: GET is the graded exercise therapy. How many people had to receive graded exercise or CBT for one person to improve?
Michael Sharpe: We have number needed to be treated. I think it's about 7 to get a clinically important treatment benefit with CBT and GET. What this trial wasn't able to answer is how much better are these treatments, and really not having very much treatment at all?
Norman Swan: What were the doctors doing for them?
Michael Sharpe: The doctors also had guidance on what to do and they do some very important things. The first thing obviously is to be clear with the patient what's wrong with them, then to give them some general guidance on not overdoing things but not resting too much and if the patient wanted to assume a self help approach, providing materials and support in doing that. The doctors would also prescribe medication for a condition such as pain, sleep problems and depression.
Norman Swan: So comparing – you've got four arms to this trial and you've said already that compared to just seeing the doctor, PACE which is the one favoured by advocacy organisations didn't add much. Was there much daylight between cognitive behavioural therapy and graded exercise therapy? In other words was one of those better than the other?
Michael Sharpe: Two things to say to that. Firstly before we say pacing, adaptive pacing therapy had no effect it didn't improve patients' fatigue or what they could do compared with medical care. But the patients who received it were as satisfied with it as the patients who received CBT and GET and that was a high level of satisfaction. So I think it is doing something for people, it's just not improving fatigue and physical functioning. Between CBT and GET there are nuances of different measures both for example one of the outcomes we did was how far the person could walk in a six minutes period and the people who had the exercise therapy did a bit better at that. The people who had the CBT did a bit better at being less depressed.
Norman Swan: Now you did something interesting at the beginning of this trial which was asking the people who came into the trial how much confidence they had in the therapy because obviously you couldn't blind this, everybody knew what they were having. You blinded the analysis so people who were doing the analysis of this didn't know what was going on but the people going in obviously knew whether or not they were just seeing a doctor or getting graded exercise therapy. So you asked them how confident they were that it was actually going to help them which to some extent goes to the placebo effect but nonetheless it just gives their expectations and they had a pretty low expectation for cognitive behavioural therapy.
Michael Sharpe: Yes. One of the reasons we did this is that after the patients had been randomised to their treatment but before they started the treatment to get some sense of how helpful they thought that course would be and that was to address just the point you say that many of the patient's expectations might affect the outcome. Importantly their expectations of pacing were good and so it means that the poor result with pacing compared to the other treatments doesn't just reflect the initial expectation. And likewise in CBT their expectation wasn't great and yet that did quite well so it does provide some support for the idea that it isn't just patients' expectations this is actually a real effect.
Norman Swan: Now I assume that one of the criticisms of the trial is that you screened I think several thousand people to get your 640 and therefore the assumption might be that there's a bit of bias that's crept in to get your 640.
Michael Sharpe: Yes, well we recruited systematically from clinics that were seeing people, patients with chronic fatigue syndrome and these are clinics where primary care doctors send patients to the specialist for an opinion. The vast majority of patients who were excluded simply didn't have chronic fatigue syndrome. So it wasn't that we were excluding thousands of people who would be eligible for the trial, these people were being sent to the clinic with a question mark and a primary care doctor said that they simply didn't have the condition.
Once you get down to the numbers who actually had the condition the rates of inclusion in the trial are very much different, I haven't worked them out precisely, but it's about what you'd expect for most trials.
Norman Swan: The response to the trial has been enormous, people are up in arms, what has been the response from your point of view?
Michael Sharpe: Well the reason to do the trial there was controversy. We have done our best to produce definitive evidence but some of the people, particularly who felt that pacing is very helpful are, I think, disappointed that the trial really didn't show much benefit of this treatment. The other reason is that cognitive behavioural therapy and graded exercise therapy have been controversial in some circles because some people feel you can't improve the condition by just changing your activity. So the field remains controversial, I think the difference is now that this trial provides really as solid an evidence as we're likely to get about just how helpful and harmful these treatments are.
Norman Swan: But there is a fundamental conceptual difference here isn't there, that the therapies that you've identified as being most helpful were ones that were focussed on an assumption that you can rehabilitate and get better from this condition whereas PACE is maybe not quite negative in terms of that there's no rehabilitation but it's not quite so positive.
Michael Sharpe: That is true in terms of emphasis and I think the theoretical conclusion from this trial would be that if you work with a therapist and do very gradual changes in what you're able to do towards rehabilitation you are able to at least in a proportion of cases improve how you feel and what you're able to do. What the trial tells us is it's worth trying this out because you can actually make some changes in your illness. You don't just have to lie back and wait for time, it's worth a try.
Norman Swan: Now you're being very calm and collected Professor Sharpe and I'm sure you haven't felt that all the way through particularly in the furore since the trial was published. Do you have any comment on what the advocacy groups, the influence that they can have on illness behaviour of the ordinary person in the street who is disabled by this condition?
Michael Sharpe: I think the first thing to say here is that we recruited 640 patients into this trial and there wasn't a high rate of refusal of taking part in the trial and those patients remarkably, a vast majority of them stayed right through to the end of the trial, they accepted the treatments and they completed our outcome data. So I think it's very important to remember that if you go out there to the clinics that most patients with chronic fatigue syndrome, all they want is the evidence for what they have to do. There is parallel to that, a very vociferous series of websites and so on, it's not really the same world as the ordinary patient coming to the clinic. They have been quite hostile in many ways to the findings of the trial and unfortunately also to the people who've undertaken the trial and collaborated with the trial.
Norman Swan: And when you say hostile to individual members of the research team, what do you mean?
Michael Sharpe: I think it's well known it's not uncommon in this field and it isn't by any means restricted to this trial or to us but people who produce findings which are not the findings that are desired we see unpleasant emails and vilification on the internet and so on.
Norman Swan: Michael Sharpe is Professor of Psychological Medicine at the University of Edinburgh. And if you want to see the treatment manuals that they used they're on the trial's website www.pacetrial.org
Richard Horton is Editor in Chief of The Lancet.
Richard Horton: We were delighted to get this trial, it was eagerly awaited. It was a remarkable study because the investigators stepped back and were willing to do an experiment comparing conventional treatments for chronic fatigue, cognitive behavioural therapy for example against a treatment which was very much endorsed by parts of the patient community but very sceptically received by the more scientific community and that was the adaptive pacing therapy. So they were really stepping back and comparing two philosophies, not just two treatments, two philosophies of what chronic fatigue syndrome was.
Norman Swan: In other words whether or not you can be rehabilitated to some extent and whether or not you should actually just adapt to the condition.
Richard Horton: Yeah, I mean adaptive pacing therapy essentially believes that chronic fatigue is an organic disease which is not reversible by changes in behaviour. Whereas cognitive behaviour therapy obviously believes that chronic fatigue is entirely reversible and these two philosophies are kind of facing off against one another in the patient community and what these scientists were trying to do is to say well, let's see, which one is right.
Norman Swan: And did you have any problems in the publishing of it?
Richard Horton: No, the paper went through peer review very successfully, it's been through endless rounds of peer review and ethical review so it was a very easy paper for us to publish. It was only at the point of publication and just after that we have had this extraordinary negative reaction.
Norman Swan: So tell me about the reaction.
Richard Horton: Well we have been deluged with dozens of letters raising serious objections to the conduct and interpretation of the study. Most recently a 43 page diatribe calling for the paper to be retracted based upon the fact that it is entirely invalid and unethical.
Norman Swan: What's the nature of the criticism?
Richard Horton: Pretty much every aspect of the study you can think of has been impugned. First of all the population is biased, it's dealing with a predominately young, healthy population whereas the chronic fatigue syndrome, ME, in a population our critics claim contains a substantial number of people who are bed ridden. Given the fact that treatments are being offered which do regard chronic fatigue as reversible then that somehow undermines the view that ME is a neurological condition. There is this feeling that ME being an organic disease in the views of some patients that means that any view that contradicts that and offers a treatment against that particular perspective must therefore by definition be unethical. So this study is we are told breaching the Declaration of Helsinki.
Norman Swan: Of course the researchers are not saying it's not organic, they are just saying that you can do something about it.
Richard Horton: This is why I think the criticisms about this study are a mirage, they obscure the fact that what the investigators did scrupulously was to look at chronic fatigue syndrome from an utterly impartial perspective.
Norman Swan: And of course this reflects the fear that advocacy groups for people with chronic fatigue syndrome have that they're going to be blamed, that they've just got psychiatric illness, you know it's all in the head and this is an invented disease is what they fear being accused of.
Richard Horton: The issue here which I still fail to understand is that nobody is claiming that chronic fatigue syndrome is an invented illness. It's taken just as seriously as any other condition.
Norman Swan: Have you had a response like this before to a paper?
Richard Horton: Not this kind of orchestrated response trying to undermine the credibility of the study from patient groups but also the credibility of the investigators and that's what I think is one of the other alarming aspects of this. This isn't a purely scientific debate; this is going to the heart of the integrity of the scientists who conducted this study.
Norman Swan: What are they saying?
Richard Horton: The accusations that are being made about them is that they have behaved unethically, breached international standards of ethics and indeed in a few examples allegations have been made to professional authorities, the General Medical Council here in the UK about the work of these scientists on the basis of the flimsiest and most unfair allegations. And indeed the study costs $4 million pounds to undertake but the allegations and the freedom of information requests and the legal fees that have been wrapped up over the years because of these vexatious claims has added another 750,000 pounds of taxpayers' money to the conduct of this study.
Norman Swan: Yet patients groups were involved, engaged in the study all the way through.
Richard Horton: Indeed, and I think this is where one sees a real fracture in the patient community. One is seeing a very substantial number of patients very willing to engage in this study, desperate to get good evidence on which to base their future treatment but one sees a fairly small, but highly organised, very vocal and very damaging group of individuals who have I would say actually hijacked this agenda and distorted the debate so that it actually harms the overwhelming majority of patients.
Norman Swan: What next?
Richard Horton: Well what we're doing right now is waiting for the formal response from the authors to this 43 page attack on their integrity and the study and the request for a retraction. We plan to publish their response to that attack, we will invite the critics to submit versions of their criticisms for publication and we will try as best as we can to conduct a reasonable scientific debate about this paper. This will be a test I think of this particular section of the patient community to engage in a proper scientific discussion.
Norman Swan: To which we will return when a more settled debate takes place. Richard Horton is Editor in Chief of The Lancet.
References:
White PD et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet March 5, 2011;377:823-36
Gijs Bleijenberg and Hans Knoop Chronic fatigue syndrome: where to PACE from here? (Comment) The Lancet March 5, 2011;377:786-788
Norman Swan has not done his homework with regard to the PACE trial it would seem. It is very sad that Richard Horton is so hostile to the groups and individuals who have taken the time to write to the lancet criticising the PACE trial. By referring to one critical letter as a “diatribe” and an “attack” hardly engenders confidence that they “will try as best as we can to conduct a reasonable scientific debate about this paper”
“Norman Swan: And the advocacy groups felt that there was some danger in graded exercise or cognitive behavioural therapy.”
What a load of tripe. They didn’t ‘feel’ anything, thei eare scientific studies with conclusions to that effect.
JT if you’re around here, I’m starting to feel like I want to take back a lot of the criticisms I angled at you.
Any sort of belief in high levels of professional ignorance or conspiracy seemed too convenient to me. Especially since it would qualify the fact that I had found GET pretty useless (certainly the way it was applied to me anyway).
I try my best to be an agnostic sufferer and have to be since the science eludes me. But you can’t help feeling sick to the stomach when you read stuff like this.
This interview just seems tantamount to incitement. They want to make people angry, it seems to serve them.
It is quiet an unbelievable situation isn’t it. I do find it difficult to comprehend myself.
This interview was a well oranised, highly vocal attempt by a very powerful group to silence scientific facts. Those facts being that the PACE trial failed for those with fatigue, not ME/CFS.
It is unworthy of anyone to even suggest that there is a group of patients who, by demanding science over ideology, have somehow damaged and distorted the “debate”. Facts do not make a debate unless you don’t use them.
Are we to take Horton’s comments as an attempt to divide the patient community on this trial? He forgets to mention the scientists, researchers and expert clinicians who also hold the same view that CBT and GET have no evidence base. That the PACE trial ingored a long history of biomedical evidence on ME/CFS and is an attempt to conjure out of existance a serious neuroimmune disease that is very possibly caused by a humman gamma retrovirus.
If the Lancet is to now regain the trust of the scientific community it must withdraw the flawed PACE trial.
One would think that a negative response of this magnitude to *any* clinical trial would result in the researchers at least opening themselves up to debate. Not so. As I’ve said elsewhere, Richard Horton appears to be practising censorship instead of editorship when it comes to PACE. It is deeply disturbing – and hugely insulting.
Morning. I can’t spend too much time as have commented on this ABC ‘well balanced and impartial’ interview elsewhere.
However, I think AFME came in for some unfair criticism following the broadcast and the broadcast itself gave the impression that AFME we wholly on-board with the Trial and the results, when this is not the case:
http://www.afme.org.uk/news.asp?newsid=1047
That the criticism afforded representative organisations and sufferers themselves, as well as experts in this field, was derisory, should go without saying.
One concern (I have mentioned elsewhere), that again does not seem to have attracted much attention, is the belittling of the Specialist Medical Care that this broadcast again emphasises.
If we didn’t have this medical intervention – the pain medications, the muscle relaxants, the sleep aids, the anti-convulsants etc. – how on earth would we even be able to consider, let alone practice, the GET and/or CBT that is prescribed?
This is the link to all the comments relating to the broadcast:
http://www.abc.net.au/rn/healthreport/stories/2011/3192571.htm
Do you mean ‘usual care’? Where you received a leaflet and a talking to, which has no evidence for being effective.
I am saying that the SMC was not a true representation of what one receives in the real world.
That GPs and Consultants actually do more than, as you put it, provide ‘a leaftlet and a talking to’.
If, for example, those taking part in the Trial were deprived of the medications received from their GPs and Consultants, and simply received ‘a leaflet and a talking to’, then the results would be even worse (in my opinion).
Therefore the Trial played down the importance of primary care and intervention. Our GPs and Consultants in the real world do far more than what you and the Trial surmise. It is insulting for them and for us.
No attempting to make any statement on your comment only the PACE trial. However, there was nothing special about SMC. It was usual care. Which means not getting much at all. They may have been allowed sleeping pills, pain killers, etc. but they were not doing anything more than an average GP. Minimum number of appointments were 3 for 30minutes each. Supposedly there were 4 GPs, 7 infectious disease physicians, and 27 liaison psychiatrists (23 who were trainees). Nothing specialist about it, which is my point. None of that is aimed at treating ME, only managing it. A doctor who thinks that those approaches are having a reversible effect on the disease would be fooling themselves.
Here is the relevant section from the PACE trial
“Specialist medical care (SMC)
SMC was provided by doctors with specialist experience in chronic fatigue syndrome (webappendix p 1). All participants were given a leaflet explaining the illness and the nature of this treatment. The manual was consistent with good medical practice, as presently recommended.2 Treatment consisted of an explanation of chronic fatigue syndrome, generic advice, such as to avoid extremes of activity and rest, specific
advice on self-help, according to the particular approach chosen by the participant (if receiving SMC alone), and symptomatic pharmacotherapy (especially for insomnia, pain, and mood).”
Thanks JT I did read the report but others may not have. I still maintain that, in the absence of specific treatment, management is the ONLY thing we have in terms of prescribed medications.
Admittedly, the protocol varies from GP to GP, consultant to consultant, with no specific drugs recommended by NICE, other than Melatonin (in the patient guide), however ‘real’ doctors on the ground trying to do their best for patients, do more than what the PACE trial implies.
A standard protocol is unlikely when a cause is not yet established, and sufferers symptoms vary in severity and priority. However, there is much that good doctors can, and do, do to help.
Hence I feel, in this respect and in others, the PACE trial belittles what good doctors and consultants are actually doing in trying to help sufferers gain some relief from their symptoms.
The whole report was written as if GET and CBT were the best thing since sliced bread, and they aren’t. They are as arbitrary as ‘symptomatic pharmacotherapy’ – among ‘good’ physicians. Again, GET should only (and PACE makes this clear), be prescribed if appropriate to the sufferers ability to manage, if you are in the severe stage of the illness, then the PACE results do not apply.
There are specific treatments from immune modulators to anti virals and more. It’s unlikely that NICE will not be offering these in the future.
I agree that not every GP is bound by the NICE guidelines. But they are making it difficult for them to stray outside. The PACE trial is an attempt to hinder what else can be done, by claiming there is no requirement for anything else, but the data cannot support this. This is all part of an attempt to keep the costs down, move the disease into a new classification and prevent serious reserach that would affect the first two. Bit late for that. HGRV’s have altered their reality.
GET shouldn’t be offered to anyone with ME as the published literature does show that it is harmful.
Interesting comments, Firestorm. I agree, if SMC did involve more than ME patients actually receive in the real world the results of the study are also very inadequate.
Also if SMC did indeed involve pain meds, sleeping meds etc, and since it is a variable treatment dependent on the individual – what is to say that patients on SMC and CBT/GET did not receive more extensive supportive interventions than patients on SMC and APT or SMC alone? The trial was not blinded after all and clinicians were not blind to the groups that patients were in.
We have already read from Professor Hooper, that some patients on CBT in the PACE trial were told that the treatment was curative, yet patients in APT were told they would not be cured. This difference alone builds in powerful bias into the trial which makes any results completely invalid.
The very reason the FDA demands drugs are compared objectively against a placebo, before license, is to find out whether the drug truly works, or whether it only works because of belief.
We know encouragement works wonders. Placebos that have bold packaging, red packaging, words like super or powerful work better than plain white placebos. All the PACE trial did was subjective ask patients if they felt better after being subject to different forms of encouragement. It wasn’t in the least bit scientific. We know the more encouragement one is given the better patients subjectively respond.
The comments of Sharpe and Horton show not just their contempt for ME patients, but their contempt at science generally. The PACE trial was not science. Subjective questionnaires are merely opinion and belief, they are not evidence. There is a flaw in most psychological research based on questionnaires. You simply cannot train a patient to feel differently about their illness and then ask a patient how they feel about their illness – of course they are going to say they feel different, that is exactly what they have been told to say.
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