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Richard Smith: QMUL and King’s college should release data from the PACE trial

16 Dec, 15 | by BMJ

richard_smith_2014Several times when I was the editor of The BMJ the journal was declared the worst medical journal in the world by an ME association. Sometimes we shared the award with The Lancet. At another time my wife was telephoned and told that if I didn’t take a different line on ME (which is better known as chronic fatigue syndrome) then “something horrible” would happen to me. So I know something about the emotion that surrounds chronic fatigue syndrome, but I still think that Queen Mary College London (QMUL) and King’s College London are making a serious mistake in refusing to release the data behind a controversial trial of treatments for chronic fatigue syndrome.

The emotion stems from sufferers from the condition resenting greatly the idea that it may have psychological causes with the stigma that implies. The resentment seems to be that psychological problems are not seen “real” in the way that physical ones are and that they may result from “moral weakness” rather than a morally neutral virus. I’ve always disliked the stigma that goes with mental illness and any idea that it is not as real or serious as physical illness. But at the same time neither I nor The BMJ had a line on the causes or treatments of chronic fatigue syndrome. We simply published what we thought was the best research on the subject that we were sent and commissioned material from the people we thought best informed on the subject. It’s true that several of those people were psychiatrists, but that didn’t mean that we thought chronic fatigue syndrome to be a psychological condition. We had open minds.

The trial that has evoked huge controversy—a Wikipedia page filled with criticisms and even questions in parliament—is called the PACE trial and was published in The Lancet in 2011. The trial compared adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome in 641 patients. Its conclusion was that cognitive behaviour therapy and graded exercise therapy moderately improved outcomes if added to specialist medical care but adaptive pacing therapy did not. These findings conflict with what many sufferers believe—that adaptive pacing therapy helps, but cognitive behaviour therapy and graded exercise therapy may lead to deterioration.

Many questions were raised about the validity of the trial, but the Medical Research Council, which funded the trial, and The Lancet stood by the trial. The authors have been not only criticised but abused.

In 2012 the cost effectiveness study from the PACE trial was published in PLOS One and found that cognitive behavioural therapy was the most cost effective treatment followed by graded exercise therapy and that adaptive pacing therapy was probably less cost effective than specialist medical care alone. Long term results were published in Lancet Psychiatry this year and showed continuing benefit from cognitive behavioural therapy and graded exercise therapy.

Kings College London and Queen Mary University of London (QMUL) own the raw data of the trials as they are the employers of the researchers. QMUL has already been asked to release the data under the Freedom of Information Act but declined, arguing that among other things that it would be possible to identify individual patients. The complainant appealed to the Information Commissioner’s Office, which dismissed the university’s arguments and ordered that the data be released. QMUL had 28 days to appeal the ruling and has presumably appealed.

In the meantime, James Coyne, a professor of psychology and a blogger for PLOS, has asked King’s College to release the data from the PLOS One study “consistent with the PLOS journals’ data sharing policies.” He wrote that he was “interested in in reproducing your empirical results, as well as conducting some additional exploratory sensitivity analyses.” These are wholly legitimate scientific practices.

King’s College on 11 December wrote to Coyne saying that it would not release the data because they considered his request “vexatious”; The Freedom of Information Act has a clause that allows a public body to decline to release data for this reason. The King’s letter is long and legalistic and comes from the Information Compliance Officer.

QMUL and King’s are making a mistake. As somebody who has been abused by people who care passionately about chronic fatigue syndrome, I can sympathise with their decision, but I still think it wrong.

Firstly, the inevitable conclusion is that they have something to hide. This is the age of transparency, and, whether people like it or not, what is not transparent is assumed to be wrong, corrupt, or biased until proved otherwise. I think of a scene from Not the 9 O’Clock News where we see pictures of a house with its roof blown off by a hurricane. “We rang the Gas Board, and they answered “no comment.’” We are led to think that the Gas Board is responsible for the hurricane.

Secondly, QMUL and King’s are going against basic scientific principles. In Popperian science we pose falsifiable hypotheses and then do all we can to tear them down. Hypothesis are never true, they are simply not falsified. This process should include other scientists being able to manipulate the data. Now it is true that “if you torture the data enough they will confess,” and those who disbelieve the results of the PACE trials will probably be able to come up with analyses that contradict the results of the trial authors.

But critics finding results that contradict those of the authors doesn’t mean they are right. Supporters of the original authors and neutral scientists can also work with the data. It’s at this point that I always wheel out my favourite quote from John Milton: “Truth was never put to the worse in a free and open encounter…. It is not impossible that she [truth] may have more shapes than one…. If it come to prohibiting, there is not ought more likely to be prohibited than truth itself, whose first appearance to our eyes bleared and dimmed with prejudice and custom is more unsightly and implausible than many errors….Where there is much desire to learn there of necessity will be much arguing, much writing, many opinions; for opinion in good men is but knowledge in the making.”

The refusal of two universities to release data relates to the current debate within universities over freedom of speech. In several universities students have stopped the appearance of speakers who have views—on, for example Islam or transgender people—that the students don’t like. This is a dangerous development. Democracies depend on free speech, and universities should be bastions of free speech—and the whole point and value of free speech is that you hear views that may disgust, distress, and anger you.

Finally, the universities may have failed to notice that customs around sharing data in science are changing rapidly. We have recognised that huge value is lost by scientists taking their datasets to the grave with them. More and more funders of research require the release of data they have funded, and journals like F1000Research require authors not just to make their data available on request but actually to submit their data with their study so that anybody can use the data either to confirm or refute the study or do other studies.

I fear that QMUL and King’s are defending the indefensible and like King Canute failing to stop a tide that is coming in fast.

Competing interest: RS was on the board of the Public Library of Science for eight years and is consulting for a fee for F1000Research.

Richard Smith was the editor of The BMJ until 2004.

Correction: The text of this blog was changed on 4 February 2016. Previously it said that “Several times when I was the editor of The BMJ the journal was declared the worst medical journal in the world by the ME (Myalgic Encephalomyelitis) Association.” The MEA pointed out that I was mistaken in saying this and that they never used this description. My apologies to the MEA. 

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  • Sasha

    Thank you for your thoughtful and timely post on this topic. I am sorry that you have been on the receiving end of abuse in relation to CFS. As one of the 250,000 ME/CFS patients in this country who have not subjected anyone to abuse and would never dream of doing so, I find it appalling that this should happen: but as you will appreciate, in such a large population of patients, we will have our fair share of those with personality disorders, just as the population of patients with cancer, arthritis or multiple sclerosis will.

    You write that “The emotion stems from sufferers from the condition resenting greatly the idea that it may have psychological causes with the stigma that implies” but I think you misunderstand why ME/CFS patients resist a psychological diagnosis. It’s simply because it’s the wrong diagnosis, and if you have an organic disease and only receive treatment directed at a psychological cause, you won’t get better: and research into your condition will be misdirected down a useless avenue.

    The prestigious US Institute of Medicine spent a year reviewing the research evidence and in its report emphasised that ME/CFS is “is a medical — not a psychiatric or psychological — illness”.

    http://www.ncbi.nlm.nih.gov/pubmed/25695122

    I’d like to see the UK establishment catch up.

  • Victor

    Thank you for writing this article, Richard. Let’s hope that reason prevails and QMUL and King’s release the data without further ado.

    I feel I need to correct a popular misconception that you have disappointingly thought fit to repeat, viz. that people with ME/CFS “resent greatly the idea that it may have psychological causes with the stigma that implies” and that their resentment seems to be founded on a belief that “psychological problems are not seen as ‘real’ in the way that physical ones are”.

    I’ve met many people with a diagnosis of ME/CFS, but not one of them has ever intimated to me that they resent the attribution of their condition to psychological causes on the grounds that “psychological problems are not seen as ‘real’ in the way that physical ones are”. What they have said, practically unanimously, is that they resent the attribution of their condition to psychological causes on the grounds that their condition, according to their privileged experience of it, does not have a psychological cause.
    The distinction is crucial, as I hope you can see.

  • Stephen Wright

    Hi Richard

    I’m heartened to hear your comments regarding the release of the PACE trial data. I agree with some of your points regarding transparency. Im sorry to hear that whilst at the BMJ your wife received an unpleasant and threatening phone call. As an ME/CFS patient for the last 10 years and Biology graduate, it is very disappointing to hear of researchers and scientists receiving threats.

    Unfortunately many patients myself included are very angry at the way ME/CFS has been dealt with over the last two-three decades, having seen years or decades go by in debilitating pain and exhaustion every day with no effective help in infact – stigmatization. Sadly amongst the thousands and thousands of people suffering severe loss of life, there will I guess be a few bad apples who cross the line from protest or criticism to more nasty behavior.

    The claim that patients with ME/CFS are anti mental illness or somehow against the attribution of it is false. This is a game that has been played to deflect criticism from the ineffective treatments of GET and CBT, and reaction against it. Yes patients with a severe (WHO defined neurological) illness do not like to have as their only treatment, one which tells you the symptoms are not as bad as you think they are. Its not much use when you are so ill you are being tube fed, cannot speak and are bedbound. All the while, the biomedical abnormalities found in smaller studies have been ignored or not given sufficient funding to replicate further, apparently because looking into them is a bad idea. If any of the people involved in this research were to be able to feel for one minute the physicality of this illness – I have no doubt it would change their view immediately. But we are stuck in this situation where because there are no current easy/cheap tests for this, that the symptoms are regarded as non-medical subjective perceptions. Bit like MS used to be I guess…? What did they call that once – female hysteria. Seems like we’ve made a retrograde step with many psychiatrists referencing ‘neurasthenia’ to support their argument…

    If there was a reasonable balance between spending on research between physical and psychological studies that would be one thing – but in the UK there has been practically no spending apart from funding these sorts of behavioural studies and the NHS support is now based upon them. The result is a reality faced by no other illness group (to my knowledge) – the most severely ill are the ones who have been worst let down. They effectively have been ignored because they are far too ill to be involved in absurd graded exercise or make it to a CBT session. This as professor Leonard Jason has said – is a moral catastrophe.

    There is and has been for years copius evidence to support these views for instance written comprehensively by Professor Malcolm Hopper in Magical Medicine:

    http://www.investinme.org/Documents/Library/magical-medicine.pdf

    With regard to funding – please see this video by ex Maths teacher and current ME patient Graham McPhee which outlines the UK spending:

    https://www.youtube.com/watch?v=j2biXfyV1bY

    Much of the source of claims against ME patients, Simon Wessely, in his own research disproved anti-mental illness theory in 1999:

    “Contrary to our hypotheses and the media accounts of CFS, we found no evidence that CFS patients are characterized by particularly hostile attitudes to mental distress….Our study also failed to demonstrate any overall differences in personality traits that may underlie negative attitudes to mental illness or psychiatry….There was no difference between CFS and RA patients in hostility to mental illness….This study provides no evidence to support the anti-psychiatry tone that is so striking in the popular literature on CFS”

    Barbara Wood and Simon Wessely; J Psychsom Res 1999:47:4:385-397

    If you would like to read a reasonable analysis of the PACE trial which describes many reasons why patients have been criticizing it please see Tullers articles on the matter.

    http://www.virology.ws/mecfs/

    I highly recommend this to get a more balanced view of the situation.

    Best wishes

  • timothy sorenson

    Hear! Hear!

  • Helle Rasmussen

    Retraction Watch about the PACE trial, with interesting comments: PLOS ONE issues editor’s note over controversial chronic fatigue syndrome research http://retractionwatch.com/2015/12/16/plos-one-issues-editors-note-over-disputed-chronic-fatigue-research/

  • Jenni

    I have ME and object to the PACE trial. But not on the grounds that I don’t wish to be thought of as having a mental health condition because I’m worried about the stigma. I don’t want to be labelled and treated as though I have a condition which I don’t in fact have. So I also wouldn’t want to be labelled and treated as though I have a heart condition (my ME causes orthostatic intolerance, which includes palpitations and raised heart rate on standing) – because I don’t.

    The PACE trial used a seriously flawed criteria for selection of participants, methodology and changed its success criteria part way through, so it was possible to be deemed ‘ill’ at the beginning and ‘recovered’ at the end while remaining the same on a
    test for functional disability. (1)

    In other countries (US and Norway) bio-medical research has identified physical differences in the brains(2) of people with ME and in the way their immune systems operate(3) and their muscles process oxygen(4).

    In Norway, two clinical trials (5) have found that a cancer drug which suppresses the immune system can move over 60% of ME patients into remission. Compare this rate of success with that of CBT /GET, even if you believe everything in the PACE trial. The Norway government apologised for their mistreatment of ME patients in light of this research(6).

    References:

    (1) http://www.virology.ws/2015/10/21/trial-by-error-i/

    http://blogs.plos.org/mindthebrain/2015/10/29/uninterpretable-fatal-flaws-in-pace-chronic-fatigue-syndrome-follow-up-study/

    (2) http://med.stanford.edu/news/all-news/2014/10/study-finds-brain-abnormalities-in-chronic-fatigue-patients.html

    (3) https://www.mailman.columbia.edu/public-health-now/news/scientists-discover-robust-evidence-chronic-fatigue-syndrome-biological

    (4) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/

    (5) http://www.ncbi.nlm.nih.gov/pubmed/19566965

    http://www.ncbi.nlm.nih.gov/pubmed/22039471

    (6) http://www.tv2.no/a/3618296 (in Norwegian, but Google will translate for you)

  • Smiffy51

    There is no more incidence of mental illness amongst people with myalgic encephalomyelitis than in the general population.

    Myalgic encephalomyelitis has been classified as a neurological illness since the 1960s. Treating it with only CBT and GET is nonsensical.

  • esthersiebert

    I am very sorry to learn that your wife received such a terrible threat and that several ME/CFS caregivers and/or patients have struck out at you and others in the UK regarding their support of the PACE studies. As mentioned below, it is important to distinguish between unconscionable threats and substantive criticism. And as an ME/CFS patient for thirty years in the US, I have not heard of such threats being issued here though there are no doubt many instances of angry verbal confrontations.

    Personally I and probably many of the up to 1 million patients in the US would have welcomed a psychological diagnosis if it had come with valid treatments and methods to show us how to recover. Alas, though we questioned our own sanity at times after being told so often that it was “all in our head,” we had to face the reality that we had a medical biological illness for which the only treatment was rest and pacing as best we could. And that this devastating debilitating illness would rob us of the rest of our lives.

    The damage the PACE studies have done and why they need to be independently reviewed is that they essentially stopped biomedical research in the UK. What I don’t understand, however, is how and why the medical establishment in England ignored the studies reviewed in the IOM report linked in a comment below for so long? I’ve always supported a single payer health system but now I wonder if one becomes bogged down in dogma which can’t be refuted in any way?

  • Simone

    Well said, John. Thank you 😊

  • Susan Hall

    I am a person who has the diagnosis of CFS who values psychology. I have put time into helping myself through the help of professional psychologists and have gained from this immensely. I still suffer from the symptoms of CFS which have changed over the years but have not been relieved by the psychological work I have done. What is difficult for me now is the fact that science is not giving me clarity on whether exercise is beneficial or harmful. I welcome more investigation being carried out on the data from the PACE Trial so that the science behind it can be either validated or discounted.

  • Mike Dean

    The uncertainty about exercise will remain whatever happens to the PACE data. PACE reported low levels of harm from GET. Patient surveys report high levels of harm. Both analyses may be biased, for different reasons. Meanwhile, the NICE guidelines recommending GET are not due for review any time soon. Patients, carers and clinicians need a neutral forum where they can meet on equal terms to formulate the most important unanswered questions about treatments. The Priority Setting Partnerships organised by the James Lind Alliance might be suitable.

  • Mike Dean

    A new PLOS ONE paper shows

    “ME/CFS patients had large changes in their symptoms of pain, fatigue, and confusion at various times post-exercise compared to controls”.

    This correlated with

    “…significant changes in the abundance of major bacterial phyla in the gut in ME/CFS patients not observed in healthy controls. In addition, compared to controls clearance of bacteria from the blood was delayed in ME/CFS patients following exercise. These findings suggest a role for an altered gut microbiome and increased bacterial translocation following exercise in ME/CFS patients that may account for the profound post-exertional malaise experienced by ME/CFS patients.”
    http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0145453

  • Peter Trewhitt

    Have several times tried to correct an error in my comment above but the ‘edit’ just seems to get lost.

    The sentence “Emotional does inevitably mean irrational” should read “Emotional does not inevitably mean irrational”. Apologies for the slip.

  • Robert Morley

    Thank you for this post, Richard, but you seem to have a misguided impression of why ME/CFS patients disagree with the results of this study. We don’t disagree with it because we “[resent] greatly the idea that it may have psychological causes with the stigma that implies”, we resent it because we KNOW that that’s simply not the case. It’s as ridiculous to me to say that my condition is psychological as it is to tell me that I’m imagining I have a broken arm, and that that’s actually a psychological condition as well.

    Let me be clear here: I suffer no stigma from the idea that I might have a psychological condition. I have Asperger’s and ADD. While perhaps not as stigmatized as other “more psychological” conditions, they are psychological conditions nevertheless and I’m quite comfortable telling the world that I have them. I am equally comfortable telling the world that I have ME/CFS…and that it is in no way psychological.

  • Peter Trewhitt

    Over the last couple of weeks l have pondered whether it is always reasonable to have an ‘open mind’. The above post states:

    “But at the same time neither I nor The BMJ had a line on the causes or treatments of chronic fatigue syndrome. We simply published what we thought was the best research on the subject that we were sent and commissioned material from the people we thought best informed on the subject. It’s true that several of those people were psychiatrists, but that didn’t mean that we thought chronic fatigue syndrome to be a psychological condition. We had open minds.”

    On the surface it seems reasonable to advocate an open mind, but is this always rational. The PACE study is based on an hypothesis, untested by the researchers, that ME/CFS is a persistence of inappropriate illness behaviour based on false cognitions. Given the number of peer reviewed studies world wide indicating ongoing physiological and/or neurological abnormalities in ME/CFS are well into the thousands, is it still rational to give equal weight to theories based on a psychological genesis? I would argue this is about as reasonable as a biologist giving equal weight to creationist as well as Darwinian theories of evolution. The world wide research findings certainly suggests it is now hardly rational to maintain an open mind on this question.

    The PACE study did not set out to test the theory of a psychological genesis and maintenance of ME/CFS, rather to test therapeutic interventions based on this now discredited hypothesis. It is possible, that despite their flawed theoretical basis there is merit in the therapies. So perhaps one could argue that though it is no longer rational to have an open mind about the rationale for CBT and GET as envisaged by the PACE study, it might be reasonable to retain an open mind on these interventions.

    Unfortunately I would argue the PACE researchers, many reviewers and commentators and policy makers have had a too open a mind, in that they have not been sufficiently critical of the PACE study. Disregarding the potentially damning methodological flaws which may make it impossible to draw any conclusions at all from the PACE data, what beyond the hype do the researchers actually claim to established? They claim to have demonstrated a degree of self reported improvement as result of CBT/GET in a sizeable group of subjects with mild to moderate chronic fatigue without any comorbidities, that this improvement does not constitute full recovery and is not mirrored in any of the ‘objective’ measures. So, as already stated ignoring the methodological flaws, keeping an open mind, it may be that these interventions help people with mild/moderate chronic fatigue ‘feel a bit better’.

    However because of their selection criteria and problems of definition it is not clear how this relates to people with the various diagnosises relating to ME/CFS in the real world, particularly those with comorbidities or severe symptoms. So far we can only relate this findings to a very limited subset of the real world patient population.

    I would argue what is important is not ‘an open mind’ rather an objective critical faculty, and that a too ‘open mind’ has given the PACE research a grossly inflated influence on the British medical and welfare establishment.

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