Sunday, 1 November 2015

PACE - Thoughts about Holes



This week Lancet Psychiatry published a long term follow-up study of the PACE trial assessing psychological interventions for Chronic Fatigue Syndrome/ME - it is available at the website following free registration

On reading it, I was struck by more questions than answers. It is clear that these follow-up data show that the interventions of Cognitive behavioural Therapy (CBT), Graded Exercise Therapy (GET) and Adaptive Pacing Therapy (APT) fare no better than Standard Medical Care (SMC). While the lack of difference in key outcomes across conditions seem unquestionable, I am more interested in certain questions thrown up by the study concerning decisions that were made and how data were presented.

A few questions that I find hard to answer from the paper...

1) How is 'unwell' defined? 
The authors state that “After completing their final trial outcome assessment, trial participants were offered an additional PACE therapy. if they were still unwell, they wanted more treatment, and their PACE trial doctor agreed this was appropriate. The choice of treatment offered (APT, CBT, or GET) was made by the patient’s doctor, taking into account both the patient’s preference and their own opinion of which would be most beneficial.” White et al 2011

But how was ‘unwell' defined in practice? Did the PACE doctors listen to patient descriptions about 'feeling unwell' at face-value or did they perhaps refer back to criteria from the previous PACE paper to define 'normal' as patient scores being “within normal ranges for both primary outcomes at 52 weeks” (CFS 18 or less and PF 60+) . Did the PACE Doctors exclude those who said they were still unwell but scored 'normally' or those who said they were well but scored poorly? None of this seems any clearer from the published protocol for the PACE trial.

Holes by Mercury Rev
Holes, dug by little moles, angry jealous
Spies, got telephones for eyes, come to you as
Friends, all those endless ends, that can't be
Tied, oh they make me laugh, an' always make me
....Cry


2) How was additional treatment decided and was it biased?
With regard to the follow-up phase, the authors also state that “The choice of treatment offered (APT, CBT, or GET) was made by the patient’s doctor, taking into account both the patient’s preference and their own opinion of which would be most beneficial”.

But what precisely informed the PACE doctors’ choice and consideration of “what would be most beneficial”?

They say “These choices were made with knowledge of the individual patient’s treatment allocation and outcome, but before the overall trial findings were known” This is intriguing …The doctors know the starting scores of their patients and the finishing scores at 52 weeks. In other words, the decision-making of PACE Doctors was non-blind, and thus informed by the consequences of the trial and how they view their patients have been progressing in each of the four conditions.


3) The authors say” Participants originally allocated to SMC in the trial were the most likely to receive additional treatment followed by those who had APT; those originally allocated to the rehabilitative therapies (CBT and GET) were less likely to receive additional treatment. In so far as the need to seek additional treatment is a marker of continuing illness, these findings support the superiority of CBT and GET as treatments for chronic fatigue syndrome.”

Because more participants were assigned further treatments following some conditions (SMC APT)rather than others (CBT GET), doesn't necessarily imply "support for superiority of CBT and GET" at all. It all depends upon the decision making process underpinning the choice made by PACE clinicians.  The trial has not been clear on whether only those who met criteria for being 'unwell' were offered additional treatment...and what were the criteria? This is especially pertinent since we already know that 13% of patients were entered into the original PACE trial who met criteria for being 'normal'


Opus 40 by Mercury Rev
"Im alive she cried, but I don't know what that means"

We know that the decision making of PACE doctors was not blind to previous treatment and outcome.
It also seems quite possible that participants who had initially been randomly assigned to SMC wanted further treatment because they were so evidently dissatisfied with being assigned to SMC rather than an intervention arm of the trial - before treatment, half of the SMC participants thought that SMC was 'not a logical treatment' for them and only 41% were confident about being helped by receiving SMC.
Such dissatisfaction would presumably be compounded by receiving a mid-trial Newsletter saying how great CBT and GET participants were faring! It appears that mid-trial, the PACE team published a newsletter for participants, which included selected patient testimonials stating how much they had benefited from “therapy” and “treatment”. The newsletter also included an article telling participants that the two interventions pioneered by the investigators and being trialled in PACE (CBT and GET) had been recommended as treatments by a U.K. government committee “based on the best available evidence.” (see http://www.meassociation.org.uk/2015/10/trial-by-error-the-troubling-case-of-the-pace-chronic-fatigue-syndrome-study-investigation-by-david-tuller-21-october-2015/)

So, we also cannot rule out the possibility that the SMC participants were also having to suffer the kind of frustration that regularly makes wait-list controls do worse than they would otherwise have done. They were presumably informed and 'consented' at the start of the trial vis-a-vis the possibility of further (different or same) therapy at the end of the trial if needed? This effectively makes SMC a wait-list control and the negative impact of such waiting in psychotherapy and CBT trials is well-documented (for a recent example http://www.nationalelfservice.net/treatment/cbt/its-all-in-the-control-group-wait-list-control-may-exaggerate-apparent-efficacy-of-cbt-for-depression/)

Let us return to the issue of how 'need' (to seek additional treatment) was defined. undoubtedly the lack of PACE Doctor blinding and the mid-trial newsletters promoting CBT ad GET, along with possible PACE Doctor research allegiance would all accord with greater numbers of CBT (and GET) referrals ...and indeed, CBT being the only therapy that was further offered to some participants - presumably after not being successful the first time!). The decisions appear to have little to do with patients showing a ‘need to seek additional treatment” and nothing at all to do with establishing "superiority of CBT and GET as treatments for chronic fatigue syndrome.”

Finally

4) perhaps I have missed something, but group outcome scores at follow-up seem quite strange. To illustrate with an example, does the follow-up SMC mean CFQ =20.2 (n=115) also include data from 6 participants who switched to APT, 23 to CBT and 14 to GET? If so, how is this any longer labelled as an SMC condition? The same goes for every other condition – they confound follow-up of intervention with change of intervention. What do such scores mean…?  And how can we now draw any meaningful conclusions about any outcomes ...under the heading of the initial group to which they were assigned?

18 comments:

  1. "This is especially pertinent since we already know that 13% of patients were entered into the original PACE trial who met criteria for being 'normal' "

    Just one clarification: the 13% only applies to one of the trial's two primary outcomes (the SF36-PF):

    http://forums.phoenixrising.me/index.php?threads/pace-trial-response-to-foi-request-numbers-within-normal-ranges-for-cfq-and-sf36-pf-at-baseline.22366/

    For patients to be described as "back to normal" by the trial's researchers following treatment, they needed to be within normal range for both primary outcomes.

    While this is just one person reporting their experience, a patient who was a part of the PACE trial recently publicly posted this:

    "I was on the PACE trial after having ME for 20+ years and I was desperate to finally be given some hope !! I was told CBT would be best for myself but was not available for a year - BUT if you help us with our PACE trial we will dangle a carrot of hope in front of you and you may be randomly selected to receive CBT… Happy Days …"

    https://www.facebook.com/permalink.php?story_fbid=958365320887793&id=171411469583186&comment_id=958411557549836&offset=0&total_comments=10&comment_tracking={%22tn%22%3A%22R2%22}

    It seemed relevant to some of your points about the SMC only group.

    It would be interesting to see how 'still unwell' was defined for this paper, especially given the loose criteria for recovery and 'back to normal' that has been used in this trial.

    Thank you for your thoughts on this.

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  2. Thanks very much for covering this topic, Professor Laws.

    The results of the 2.5-year follow-up don't show that GET, CBT and APT fare no better than SMC (specialised medical care) - they show that GET, CBT and APT had no effect at all.

    PACE had four arms:

    SMC
    SMC + APT
    SMC + CBT
    SMC + GET

    So the lack of difference between groups at long-term follow-up shows that those therapies are null. But the results have been spun by the authors to suggest the opposite, I'm afraid.

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  3. Professor Laws, you raise a very interesting point when you ask whether the study authors used their calculated "normal ranges" for physical function and fatigue to tell if patients were still "unwell".

    Astonishingly, the threshold for the physical function "normal range" is so low at 60/100 on the SF-36 scale that it is below the level of trial entry (65) and similar to the mean score of patients with Class II congestive heart failure.

    The PACE authors used it - and a fatigue "normal range" threshold with similar problems - to draw conclusions about clinical effectiveness (in their 2011 Lancet paper) and about recovery from CFS (in their 2013 Psychological Medicine paper).

    This petition, asking the journals to retract these misleading analyses, has gained over 5,500 signatures in four days. I hope that you and your readers will sign. Pages linked from the petition give background detail that any scientist - especially psychologist - will be horrified to read.

    I've cross-checked the information on those pages against the original papers and it is accurate.

    http://my.meaction.net/petitions/pace-trial-needs-review-now

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  4. Thank you for covering this. Very interesting read. In case you haven't seen it, here is the CBT manual, which those caring for the participants were also encouraged to read as well as patients: http://www.wolfson.qmul.ac.uk/images/pdfs/4.cbt-participant-manual.pdf
    Participants are told that the treatment will work and is safe in CFS/ME, before they've even had it, even though that is what the study is supposed to be trying to assess! "Cognitive behaviour therapy (CBT) is a powerful and safe treatment which has been shown to be effective in a variety of illnesses, including CFS/ME, headaches and back pain."
    For supporters of participants, who are roped in to further control participants beliefs about the treatment, it contains directions on telling participants that any increase in symptoms they may experience is "temporary" and that most people's symptoms later decrease. Setbacks are described as a "blip" in the recovery phase and "certainly do not mean that CBT has failed." it then goes on to suggest that any increase in symptoms can be put down to something else outside of the illness. These are just a few very quick highlights. There are many more in there. Surely telling the participants and their supporters what to think about the treatment before the study is over, is a major no no. Yet not only did the authors see no issue with it, neither did their ethics panel which gave it the green light.
    I have followed you on twitter and look forward to reading anything more you write on the topic.

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  5. In case of help, here are some extracts from the CBT participants manual which seem designed to evoke the placebo response

    http://www.wolfson.qmul.ac.uk/images/pdfs/4.cbt-participant-manual.pdf

    Manual for Participants
    COGNITIVE BEHAVIOUR THERAPY for CFS/ME
    Mary Burgess Trudie Chalder

    This manual aims to provide you with useful information and strategies to help you to overcome your chronic fatigue syndrome (CFS)/ myalgic encephalitis/encephalopathy (ME). Many of the strategies described in the manual are based on cognitive behaviour therapy, which has been shown to be effective in treating a wide range of problems, including CFS/ME.


    The information has been set out in an order that is commonly used by people to overcome their CFS/ME.


    CBT is designed to help you to discover the most useful ways of managing and overcoming your illness.



    Remember- the benefits of continuing with cognitive behaviour therapy makes overcoming the difficulties worthwhile


    Setting targets is a very important step in helping you to overcoming your CFS/ME.


    Hopefully this manual and your sessions of cognitive behaviour therapy will have helped you to find some useful ways of managing your CFS/ME and you will be well on your way to recovery.


    Cognitive behaviour therapy (CBT) is a powerful and safe treatment which has been shown to be effective in a variety of illnesses, including CFS/ME, headaches and back pain.



    Many people have successfully overcome CFS/ME using cognitive behaviour therapy, and have maintained and consolidated their improvement once treatment has ended



    As long as a good balance of activity and rest is maintained, then recovery will be sustained.

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  6. And here are some quotes from the manual given to the GET participants. Sorry I forgot to say, thank you so much for looking into the PACE issue, really appreciated.

    (URL: http://www.wolfson.qmul.ac.uk/images/pdfs/6.get-participant-manual.pdf)

    GRADED EXERCISE THERAPY
    Information for Participants
    Bavinton J, Dyer N, White PD

    GET can help by building muscle strength, which in turn allows you to do more.


    GET can help by improving fitness and the efficiency of your cardiovascular system.


    GET can help by improving your ability to undertake physical activities.


    GET can help by challenging your body physically, which can lead to improved coordination and balance.


    GET has been shown to improve mental functioning.


    Graded Exercise Therapy for CFS/ME has been shown to improve thinking ability, or cognition.


    If you would love to be able to walk your children to school or get back to playing a sport you enjoy, GET helps you to gradually build up your strength and fitness to achieve this.


    In previous research studies, most people with CFS/ME felt either ‘much better’ or ‘very much better’ with GET.

    Exercise has been considered a useful strategy for many years in the rehabilitation of fibromyalgia, Multiple Sclerosis, and many other neurological conditions. Research has now shown that carefully graded exercise (Graded Exercise Therapy) can also be a very helpful therapy for CFS/ME. You may be aware that the Chief Medical Officer’s Report of 2002 recommended GET as one of the most effective therapy strategies currently known.


    There is nothing to stop your body from gaining strength and fitness, as long as it is done in a carefully monitored way, relating directly with your own particular circumstances – started and progressed at the right rate for you. Good luck!


    Your improvements will continue as long as you maintain your level of activity and exercise.


    GET is the use of regular, physical exercise to aid recovery from CFS/ME.


    As long as a good balance of activity and rest is maintained, then recovery will be sustained.

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  7. I just wanted to sincerely thank you for covering this subject and looking more closely at this study. I suffer from ME and have done so since I was a teenager. During that time I undertook a course of very mild physiotherapy that made me much worse and began a downward spiral that resulted in me being in a wheelchair and bed bound. I greatly worry about research into GET and CBT and subsequent treatment advisc based on it that does not reflect the experiences of people like me, and there are many of us. We are truly heartened by any analysis of The PACE trial as we know the risks of exercise treatments for some people with ME can be large and want to prevent others ending in this dismal place.Just to say, if a robust paper were to be released deeming it safe I would be encouraged to hope it might work but I don't feel this paper is it. From me and people like me, thank you.

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  8. Thank you for writing this piece, Professor Laws. Patients appreciate scientific contribution from those who are out of the field.

    What is critical to know is that the psych lobby empire shared the PACE trial ad nauseum in the media for decades now. Physicians from around the world, except for a handful, have used the PACE trial and believed the psychiatrists when they said patients had false illness beliefs and that the disease is due to childhood abuse.

    On the other hand, this handful of physicians who have dared listening to the patients, are convinced that the disease that we have is no fiction, and that there is either an unknown pathogen involved or an abnd mal immune response to the initial infection, often time but not always EBV (Epstein Barr virus). The psych lobby has successfully delayed and prevented governments to fund this disease.

    Patients from around the world suffer from stigma in society as well as in health care due to the way the psych lobby has managed this illness. Some, like Danish woman Karina Hansen has been taken, kidnapped if you will from her parents home and forced into CBT and GET against her and her family's will. Her parents are forbidden to even visit her. Karina is too sick to even speak.

    An analysis of the perverted PACE trial and subsequent paper from you means that the info is reaching out to other part of the society and hopefully scientific and medical world and this is much needed, so i thank you very much.



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  9. A very good article, thank you! One quick point:

    Regarding the SMC/APT groups potentially improving due to post-trial CBT/GET, there is relevant data in the supplementary materials at http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366%2815%2900317-X/supplemental

    Page 4 gives the fatigue and physical functioning questionnaire scores, broken down by post-trial CBT/GET received by the patients in each arm of the study. That data shows that there is no difference for the SMC/APT patients who received 10+, 1-9, or 0 episodes of CBT/GET.

    Hence it seems that their hypothesis in that regard has already been disproven by their own data.

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  10. Thank you Professor Laws for this blog. As someone with ME I find it very hard to retain facts for very long let alone to read and understand a paper that only came out last week, so your efforts here are gratefully appreciated.

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  11. Thank you so much for this blog. As a severely affected ME patient who was rendered permanently disabled by Graded Exercise Therapy, I am personally indebted to any academic who can highlight the flaws in this trial.

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  12. I was on the PACE trial. I was part of the late intake of participants and was in the CBT + APT arm of the trial. I've seen references in other places stating participants only received CBT with GET. This is not true and is an important point.

    I walked into the trial with a stick and moderate M.E. still managing to work part time. My course was 6 weeks long, 2hrs a week. I came top of my group for CBT and was told this is how you are treated with ME that by changing your attitude and responses to things you will improve. So I complied.

    19th December 2011, 3 days after the end of the course I collapsed from the effort of getting to it. I've been 80% housebound and periodically bedbound in relapses ever since. I cannot comply with anything now.

    Words are insufficient to express the gratitude to you and other academics who are coming out to highlight to the world the flaws in this trial. The authors of this trial have been the leading voice of ME in the UK since the 1980s. These are the same people whose press releases back then sparked the 'all in the mind' and 'yuppie flu' headlines. The authors do not have to live with the consequences of their actions. Please help to make this abuse stop.

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    Replies
    1. I'm so sorry to hear this Julie. Were you one of the respondents in the follow up (relating to the most recent article in the Lancet)? I wonder whether some of the people who didn't respond were too ill to do so?

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  13. At 16 mins, speaking about the PACE trial, Simon Wessely says: "It was the "final, kind of, definitive trial... I'm not connected with this trial. I recruited some patients for it but I was not part of it... I wish I had been...because it's a genuinely beautiful trial. It's one of the most beautiful behavioural medicine trials that we've ever seen... So, it's a fantastic and beautiful trial... We've improved the physical health, the psychological health, functioning and so on of a large number of people... It's also incredibly safe despite some of the things that's been said about it... these are very, very, safe treatments."

    http://www.foundation.org.uk/Events/AudioPdf.aspx?s=1200&f=20110504_Wessely.pdf


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  14. Thank you for writing about this.

    I have a question that has not yet been answered. I know from previous studies done by those who favor CBT/GET that when a patient had to drop out of the study because their conditioned worsened so strongly (usually from GET), the authors made no note of it. I know this because I had friends who were IN the studies, who collapsed in the middle, and could not continue - I knew about 3, so there must have been at least three, but they were never reported.

    So I wondered if something similar happened this time. For those of us who have the disease, it is not believable that every patient who really had M.E. (many did not - they had primary depression or anxiety) could make it through the course of treatment. Yet I did not see any discussion by the authors of patients dropping out - even though, in practice, they have developed a new psychiatric term for it, "Persistent Refusal Syndrome."

    I experienced something similar when my insurance company required me to undergo testing to see if I was fit for employment. I had to go for two days - and, in fact, I was on medication and thought i was doing well. I had to walk up an down about five steps, handwrite something, kneel for a bit, type something, and do a few other simple tasks that would be easy for a normal person. I was supposed to keep repeating it until the morning or afternoon time was up. On the second day, I blacked out in the middle of one of the tasks. I remember coming around with the investigator nudging me with her foot, saying "You have to go - it's closing time." Fortunately, my husband was working nearby and he could pick me up and drive me home (and have a colleague drive my car home). I did not do well the next few days - and a month later, I had a complete collapse.

    When I went to the IME (Independent Medical Exam), the doctor had the results in front of him and we asked what it said. The examiner had written down that i had "quit" in the middle of the study, as if it were voluntary.

    so I have wondered why there seems to be no record of anybody "quitting." Does anybody know?

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  15. Simon Wessely has responded on the Mental Elf. With a nautical metaphor. Or something. He doesn't seem to share any critical views on the study. Shocking.

    http://www.nationalelfservice.net/other-health-conditions/chronic-fatigue-syndrome/the-pace-trial-for-chronic-fatigue-syndrome-choppy-seas-but-a-prosperous-voyage/

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  16. Thank you for your blog. Perhaps you are not the right person to ask, but I can't help but wonder how these psychiatrists profited from their findings in relation to the NHS and the disability insurance industry? Has anyone investigated this angle of the story?

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  17. If it wasn't such a serious topic it would be a great farce he has written. But like the titanic the pace trial is sinking in its own blindness to its weakness. One day the uk government and medical society will have to apologise for the harm they have caused so many innocent victims. Just like they had to people with MND, Parkinson's Disease and MS. I am waiting patiently.

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