Earlier decisions by the investigator group preclude valid long-term follow-up evaluation of CBT for chronic fatigue syndrome (CFS).
At the outset, let me say that I’m skeptical whether we can hold the PACE investigators responsible for the outrageous headlines that have been slapped on their follow-up study and on the comments they have made in interviews.
The Telegraph screamed
Chronic Fatigue Syndrome sufferers ‘can overcome symptoms of ME with positive thinking and exercise’
Oxford University has found ME is not actually a chronic illness
My own experience critiquing media interpretation of scientific studies suggests that neither researchers nor even journalists necessarily control shockingly inaccurate headlines placed on otherwise unexceptional media coverage. On the other hand, much distorted and exaggerated media coverage starts with statements made by researchers and by press releases from their institutions.
The one specific quote attributed to a PACE investigator is unfortunate because of its potential to be misinterpreted by professionals, persons who suffer from chronic fatigue syndrome, and the people around them affected by their functioning.
“It’s wrong to say people don’t want to get better, but they get locked into a pattern and their life constricts around what they can do. If you live within your limits that becomes a self-fulfilling prophesy.”
It suggests that willfulness causes CFS sufferers’ impaired functioning. This is ridiculous as application of the discredited concept of fighting spirit to cancer patients’ failure to triumph against their life altering and life-threatening condition. Let’s practice the principle of charity and assume this is not the intention of the PACE investigator, particularly when there is so much more for which we should give them responsibility.
Go here for a fuller evaluation that I endorse of the Telegraph coverage of PACE follow-up study.
Having read the PACE follow-up study carefully, my assessment is that the data presented are uninterpretable. We can temporarily suspend critical thinking and some basic rules for conducting randomized trials (RCTs), follow-up studies, and analyzing the subsequent data. Even if we do, we should reject some of the interpretations offered by the PACE investigators as unfairly spun to fit what has already a distorted positive interpretation o
f the results.
It is important to note that the PACE follow-up study can only be as good as the original data it’s based on. And in the case of the PACE study itself, a recent longread critique by UC Berkeley journalism and public health lecturer David Tuller has arguably exposed such indefensible flaws that any follow-up is essentially meaningless. See it for yourself [1, 2, 3 ].
This week’s report of the PACE long term follow-up study and a commentary are available free at the Lancet Psychiatry website after a free registration. I encourage everyone to download a copy before reading further. Unfortunately, some crucial details of the article are highly technical and some details crucial to interpreting the results are not presented.
I will provide practical interpretations of the most crucial technical details so that they are more understandable to the nonspecialist. Let me know where I fail.
To encourage proceeding with this longread, but to satisfy those who are unwilling or unable to proceed, I’ll reveal my main points are
- The PACE investigators sacrificed any possibility of meaningful long-term follow-up by breaking protocol and issuing patient testimonials about CBT before accrual was even completed.
- This already fatal flaw was compounded with a loose recommendation for treatment after the intervention phase of the trial ended. The investigators provide poor documentation of which treatment was taken up by which patients and whether there was crossover in the treatment being received during follow up.
- Investigators’ attempts to correct methodological issues with statistical strategies lapses into voodoo statistics.
- The primary outcome self-report variables are susceptible to manipulation, investigator preferences for particular treatments, peer pressure, and confounding with mental health variables.
- The Pace investigators exploited ambiguities in the design and execution of their trial with self-congratulatory, confirmatory bias.
The Lancet Psychiatry summary/abstract of the article
Background. The PACE trial found that, when added to specialist medical care (SMC), cognitive behavioural therapy (CBT), or graded exercise therapy (GET) were superior to adaptive pacing therapy (APT) or SMC alone in improving fatigue and physical functioning in people with chronic fatigue syndrome 1 year after randomisation. In this pre-specified follow-up study, we aimed to assess additional treatments received after the trial and investigate long-term outcomes (at least 2 years after randomisation) within and between original treatment groups in those originally included in the PACE trial.
Findings Between May 8, 2008, and April 26, 2011, 481 (75%) participants from the PACE trial returned questionnaires. Median time from randomisation to return of long-term follow-up assessment was 31 months (IQR 30–32; range 24–53). 210 (44%) participants received additional treatment (mostly CBT or GET) after the trial; with participants originally assigned to SMC alone (73 [63%] of 115) or APT (60 [50%] of 119) more likely to seek treatment than those originally assigned to GET (41 [32%] of 127) or CBT (36 [31%] of 118; p<0·0001). Improvements in fatigue and physical functioning reported by participants originally assigned to CBT and GET were maintained (within-group comparison of fatigue and physical functioning, respectively, at long-term follow-up as compared with 1 year: CBT –2·2 [95% CI –3·7 to –0·6], 3·3 [0·02 to 6·7]; GET –1·3 [–2·7 to 0·1], 0·5 [–2·7 to 3·6]). Participants allocated to APT and to SMC alone in the trial improved over the follow-up period compared with 1 year (fatigue and physical functioning, respectively: APT –3·0 [–4·4 to –1·6], 8·5 [4·5 to 12·5]; SMC –3·9 [–5·3 to –2·6], 7·1 [4·0 to 10·3]). There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up.
Interpretation The beneficial effects of CBT and GET seen at 1 year were maintained at long-term follow-up a median of 2·5 years after randomisation. Outcomes with SMC alone or APT improved from the 1 year outcome and were similar to CBT and GET at long-term follow-up, but these data should be interpreted in the context of additional therapies having being given according to physician choice and patient preference after the 1 year trial final assessment. Future research should identify predictors of response to CBT and GET and also develop better treatments for those who respond to neither.
Note the contradiction here which will persist throughout the paper, the official Oxford University press release, quotes from the PACE investigators to the media, and media coverage. On the one hand we are told:
Improvements in fatigue and physical functioning reported by participants originally assigned to CBT and GET were maintained…
Yet we are also told:
There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up.
Which statement is to be given precedence? To the extent that features of a randomized trial have been preserved in the follow-up (which we will see, is not actually the case), a lack of between group differences at follow-up should be given precedence over any persistence of change within groups from baseline. That is a not controversial point for interpreting clinical trials.
A statement about group differences at follow up should proceed and qualify any statement about within-group follow up. Otherwise why bother with a RCT in the first place?
The statement in the Interpretation section of the summary/abstract has an unsubstantiated spin in favor of the investigators’ preferred intervention.
Outcomes with SMC alone or APT improved from the 1 year outcome and were similar to CBT and GET at long-term follow-up, but these data should be interpreted in the context of additional therapies having being given according to physician choice and patient preference after the 1 year trial final assessment.
If we’re going to be cautious and qualified in our statements, there are lots of other explanations for similar outcomes in the intervention and control groups that are more plausible. Simply put and without unsubstantiated assumptions, any group differences observed earlier have dissipated. Poof! Any advantages of CBT and GET are not sustained.
How the PACE investigators destroyed the possibility of an interpretable follow-up study
Neither the Lancet Psychiatry article nor any recent statements by the PACE investigators acknowledged how these investigators destroyed any possibility of analyses of meaningful follow-up data.
Before the intervention phase of the trial was even completed, even before accrual of patients was complete, the investigators published a newsletter in December 2008 directed at trial participants. An article appropriately reminds participants of the upcoming two and one half year follow-up. But then it acknowledges difficulty accruing patients, but that additional funding has been received from the MRC to extend recruiting. And then glowing testimonials appear on p. 3 of the newsletter about the effects of their intervention.
“Being included in this trial has helped me tremendously. (The treatment) is now a way of life for me, I can’t imagine functioning fully without it. I have nothing but praise and thanks for everyone involved in this trial.”
“I really enjoyed being a part of the PACE Trial. It helped me to learn more about myself, especially (treatment), and control factors in my life that were damaging. It is difficult for me to gauge just how effective the treatment was because 2007 was a particularly strained, strange and difficult year for me but I feel I survived and that the trial armed me with the necessary aids to get me through. It was also hugely beneficial being part of something where people understand the symptoms and illness and I really enjoyed this aspect.”
These testimonials are a horrible breach of protocol. Taken together with the acknowledgment of the difficulty accruing patients, the testimonials solicit expression of gratitude and apply pressure on participants to endorse the trial by providing a positive of their outcome. Some minimal effort is made to disguise the conditions from which the testimonials come. However, references to a therapist and, in the final quote above, to “control factors in my life that were damaging” leave no doubt that the CBT and GET favored by the investigators is having positive results.
Probably more than in most chronic illnesses, CFS sufferers turn to each other for support in the face of bewildering and often stigmatizing responses from the medical community. These testimonials represent a form of peer pressure for positive evaluations of the trial.
Any investigator group that would deliberately violate protocol in this manner deserves further scrutiny for other violations and threats to the validity of their results. I challenge defenders of the PACE study to cite other precedents for this kind of manipulation of clinical trials participants. What would they have thought if a drug company had done this for the evaluation of their medication?
The breakdown of randomization as further destruction of the interpretability of follow-up results
Returning to the Lancet Psychiatry article itself, note the following:
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. These choices were made with knowledge of the individual patient’s treatment allocation and outcome, but before the overall trial findings were known. Interventions were based on the trial manuals, but could be adapted to the patient’s needs.
Readers who are methodologically inclined might be interested in a paper in which I discuss incorporating patient preference in randomized trials, as well as another paper describing clinical trial conducted with German colleagues in which we incorporated patient preference in evaluation of antidepressants and psychotherapy for depression in primary care. Patient preference can certainly be accommodated in a clinical trial in ways that preserve the benefits of randomization, but not as the PACE investigators have done.
Following completion of the treatment to which particular patients were randomly assigned, the PACE trial offered a complex negotiation between patient and trial physician about further treatment. This represents a thorough breakdown of the benefits of a controlled randomized trial for the evaluation of treatments. Any focus on the long-term effects of initial randomization is sacrificed by what could be substantial departures from that randomization. Any attempts at statistical corrections will fail.
Of course, investigators cannot ethically prevent research participants from seeking additional treatment. But in the case of PACE, the investigators encouraged departures from the randomized treatment yet did not adequately take into account the decisions that were made. An alternative would have been to continue with the randomized treatment, taking into account and quantifying any cross over into another treatment arm.
Voodoo statistics in dealing with incomplete follow-up data.
Between May 8, 2008, and April 26, 2011, 481 (75%) participants from the PACE trial returned questionnaires.
This is a very good rate of retention of participants for follow-up. The serious problem is that neither
- loss to follow-up nor
- whether there was further treatment, nor
- whether there was cross over in the treatment received in follow-up versus the actual trial
is random.
Furthermore, any follow-up data is biased by the exhortation of the newsletter.
No statistical controls can restore the quality of the follow-up data to what would’ve been obtained with preservation of the initial randomization. Nothing can correct for the exhortation.
Nonetheless, the investigators tried to correct for loss of participants to follow-up and subsequent treatment. They described their effort in a technically complex passage, which I will subsequently interpret:
We assessed the differences in the measured outcomes between the original randomised treatment groups with linear mixed-effects regression models with the 12, 24, and 52 week, and long-term follow-up measures of outcomes as dependent variables and random intercepts and slopes over time to account for repeated measures.
We included the following covariates in the models: treatment group, trial stratification variables (trial centre and whether participants met the international chronic fatigue syndrome criteria,3 London myalgic encephalomyelitis criteria,4 and DSM IV depressive disorder criteria),18,19 time from original trial randomisation, time by treatment group interaction term, long-term follow-up data by treatment group interaction term, baseline values of the outcome, and missing data predictors (sex, education level, body-mass index, and patient self-help organisation membership), so the differences between groups obtained were adjusted for these variables.
Nearly half (44%; 210 of 479) of all the follow-up study participants reported receiving additional trial treatments after their final 1 year outcome assessment (table 2; appendix p 2). The number of participants who received additional therapy differed between the original treatment groups, with more participants who were originally assigned to SMC alone (73 [63%] of 115) or to APT (60 [50%] of 119) receiving additional therapy than those assigned to GET (41 [32%] of 127) or CBT (36 [31%] of 118; p<0·0001).
In the trial analysis plan we defined an adequate number of therapy sessions as ten of a maximum possible of 15. Although many participants in the follow-up study had received additional treatment, few reported receiving this amount (table 2). Most of the additional treatment that was delivered to this level was either CBT or GET.
The “linear mixed-effects regression models” are rather standard techniques for compensating for missing data by using all of the available data to estimate what is missing. The problem is that this approach assumes that any missing data are random, which is an untested assumption that is unlikely to be true in this study.
The inclusion of “covariates” is an effort to control for possible threats to the validity of the overall analyses by taking into account what is known about participants. There are numerous problems here. We can’t be assured that the results are any more robust and reliable than what would be obtained without these efforts at statistical control. The best publishing practice is to make the unadjusted outcome variables available and let readers decide. Greatest confidence in results is obtained when there is no difference between the results in the adjusted and unadjusted analyses.
Methodologically inclined readers should consult an excellent recent article by clinical trial expert, Helene Kraemer, A Source of False Findings in Published Research Studies Adjusting for Covariates.
The effectiveness of statistical controls depends on certain assumptions being met about patterns of variation within the control variables. There is no indication that any diagnostic analyses were done to determine whether possible candidate control variables should be eliminated in order to avoid a violation of assumptions about the multivariate distribution of covariates. With so many control variables, spurious results are likely. Apparent results could change radically with the arbitrary addition or subtraction of control variables. See here for a further explanation of this problem.
We don’t even know how this set of covariate/control variables, rather than some other set, was established. Notoriously, investigators often try out various combinations of control variables and present only those that make their trial looked best. Readers are protected from this questionable research practice only with pre-specification of analyses before investigators know their results—and in an unblinded trial, researchers often know the result trends long before they see the actual numbers.
See JP Simmons’ hilarious demonstration that briefly listening to the Beatles’ “When I’m 64” can be leave research participants a year and a half older younger than listening to “Kalimba” – at least when investigators have free reign to manipulate the results they want in an study without pre-registration of analytic plans.
Finally, the efficacy of complex statistical controls is widely overestimated and depends on unrealistic assumptions. First, it is assumed that all relevant variables that need to be controlled have been identified. Second, even when this unrealistic assumption has been met, it is assumed that all statistical control variables have been measured without error. When that is not the case, results can appear significant when they actually are not. See a classic paper by Andrew Phillips and George Davey Smith for further explanation of the problem of measurement error producing spurious findings.
What the investigators claim the study shows
In an intact clinical trial, investigators can analyze outcome data with and without adjustments and readers can decide which to emphasize. However, this is far from an intact clinical trial and these results are not interpretable.
The investigators nonetheless make the following claims in addition to what was said in the summary/abstract.
In the results the investigators state
The improvements in fatigue and physical functioning reported by participants allocated to CBT or GET at their 1 year trial outcome assessment were sustained.
This was followed by
The improvements in impairment in daily activities and in perceived change in overall health seen at 1 year with these treatments were also sustained for those who received GET and CBT (appendix p 4). Participants originally allocated to APT reported further improvements in fatigue, physical functioning, and impairment in daily activities from the 1 year trial outcome assessment to long-term follow-up, as did those allocated to SMC alone (who also reported further improvements in perceived change in overall health; figure 2; table 3; appendix p 4).
If the investigators are taking their RCT design seriously, they should give precedence to the null findings for group differences at follow-up. They should not be emphasizing the sustaining of benefits within the GET and CBT groups.
The investigators increase their positive spin on the trial in the opening sentence of the Discussion
The main finding of this long-term follow-up study of the PACE trial participants is that the beneficial effects of the rehabilitative CBT and GET therapies on fatigue and physical functioning observed at the final 1 year outcome of the trial were maintained at long-term follow-up 2·5 years from randomisation.
This is incorrect. The main finding is that any reported advantages of CBT and GET at the end of the trial were lost by long-term follow up. Because an RCT is designed to focus on between group differences, the statement about sustaining of benefits is post-hoc.
The Discussion further states
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.
This makes unwarranted and self-serving assumptions that treatment choice was mainly driven by the need for further treatment, when decision-making was contaminated by investigative preference, as stated in the newsletter. Note also that CBT is a novel treatment for research participants and more likely to be chosen on the basis of novelty alone in the face of overall modest improvement rates for the trial and lack of improvements in objective measures. Whether or not the investigators designate a limited range of self-report measures as primary, participant decision-making may be driven by other, more objective measures.
Regardless, investigators have yet to present any data concerning how decisions for further treatment were made, if such data exist.
The investigators further congratulate themselves with
There was some evidence from an exploratory analysis that improvement after the 1 year trial final outcome was not associated with receipt of additional treatment with CBT or GET, given according to need. However this finding must be interpreted with caution because it was a post-hoc subgroup analysis that does not allow the separation of patient and treatment factors that random allocation provides.
However, why is this analysis singled out has exploratory and to be interpreted with caution because it is a post-hoc subgroup analysis when similarly post-hoc subgroup analyses are recommended without such caution?
The investigators finally get around to depicting what should be their primary finding, but do so in a dismissive fashion.
Between the original groups, few differences in outcomes were seen at long-term follow-up. This convergence in outcomes reflects the observed improvement in those originally allocated to SMC and APT, the possible reasons for which are listed above.
The discussion then discloses a limitation of the study that should have informed earlier presentation and discussion of results
First, participant response was incomplete; some outcome data were missing. If these data were not missing at random it could have led to either overestimates or underestimates of the actual differences between the groups.
This minimizes the implausibility of the assumption of random missing variables, as well as the problems introduced by the complex attempts to control confounds statistically.
And then there is an unsubstantiated statement that is sure to upset persons who suffer from CFS and those who care for them.
the outcomes were all self-rated, although these are arguably the most pertinent measures in a condition that is defined by symptoms.
I could double the length of this already lengthy blog post if I fully discussed this. But let me raise a few issues.
- The self-report measures do not necessarily capture subjective experience, only forced choice responses to a limited set of statements.
- One of the two outcome measures, the physical health scale of the SF-36 requires forced choice responses to a limited set of statements selected for general utility across all mental and physical conditions. Despite its wide use, the SF-36 suffers from problems in internal consistency and confounding with mental health variables. Anyone inclined to get excited about it should examine its items and response options closely. Ask yourself, do differences in scores reliably capture clinically and personally significant changes in the experience and functioning associated with the full range of symptoms of CHF?
- The validity other primary outcome measure, the Chalder Fatigue Scale depends heavily on research conducted by this investigator group and has inadequate validation of its sensitivity to change in objective measures of functioning.
- Such self-report measures are inexorably confounded with morale and nonspecific mental health symptoms with large, unwanted correlation tendency to endorse negative self-statements that is not necessarily correlated with objective measures.
Although it was a long time ago, I recall well my first meeting with Professor Simon Wessely. It was at a closed retreat sponsored by NIH to develop a consensus about the assessment of fatigue by self-report questionnaire. I listened to a lot of nonsense that was not well thought out. Then, I presented slides demonstrating a history of failed attempts to distinguish somatic complaints from mental health symptoms by self-report. Much later, this would become my “Stalking bears, finding bear scat in the woods” slide show.
But then Professor Wessely arrived at the meeting late, claiming to be grumbly because of jet lag and flight delays. Without slides and with devastating humor, he upstaged me in completing the demolition of any illusions that we could create more refined self-report measures of fatigue.
I wonder what he would say now.
But alas, people who suffer from CFS have to contend with a lot more than fatigue. Just ask them.
[To be continued later if there is interest in my doing so. If there is, I will discuss the disappearance of objective measures of functioning from the PACE study and you will find out why you should find some 3-D glasses if you are going to search for reports of these outcomes.]
Thank you very much for writing this!
PLEASE(!!!) continue!
Thank you for the encouragement. There is so much more to say.
Please don’t hold back. Judging from the Borg heart rate graph, I take it that you’re aware of the discrepancy between the objective and subjective measures. There is however another elephant in the room which is the reporting of adverse events. In a ME association survey, 74% of patients reported worse health after participating in a course of graded exercise therapy. To my knowledge the authors have never acknowledged the severity and frequency of adverse events. Either they’re studying a very different patient population, the graded exercise therapy in the real world is totally different from the one in studies, or they’re doing their best to look the other way. Any of these is a big problem.
http://www.meassociation.org.uk/2015/05/23959/
At 1hr 39 mins, Sharpe says of CBT and GET that there is: “no evidence that they cause deterioration or harm” and that this is “new information” he says. Then again at 1hr 41 mins:”… there isn’t a risk of harm”.
What measures did they take to record adverse events during the trial? From reading personal accounts of trial participants, a great deal of harm was done but went unacknowledged and unreported by those conducting the trial.
Quoted from: http://www.bbc.co.uk/iplayer/episode/b06jt5k3/victoria-derbyshire-28102015
101 good reasons why it is wrong to provide CBT and GET to ME Patients – an excellent resource: http://carersfight.blogspot.co.uk/2010/03/101-good-reasons.html
Many thanks for getting involved, Dr Coyne – you are undoubtedly providing positivity in our community that will save lives.
You’re right, Leo, the smell from this particular elephant can’t be ignored any longer. The Lancet paper shows twice as many serious adverse events (SAEs) in the GET group as in the other three groups but didn’t draw attention to the problem. This is in line with the surveys that have consistently found GET bad for patients:
http://www.meassociation.org.uk/wp-content/uploads/2015-ME-Association-Illness-Management-Report-No-decisions-about-me-without-me-30.05.15.pdf
The PACE authors did not discuss adverse events until two years later in a PACE satellite paper in the J Psychosomatic Res
http://www.sciencedirect.com/science/article/pii/S0022399914001883
This time they reported no difference in SAEs between groups but they failed to mention that the protocol definition of SAEs had been changed. A requirement of a 20+ point reduction in the SF-36 score was changed from one assessment point to two consecutive assessment points. Bear in mind the gap of 7 months between points 2 and 3. Even then there were still many more SAEs in the GET arm. Assessors unblinded to treatment were then allowed to remove the SAEs in the GET group by attributing them to other causes than GET.
A different sort of manipulation also affected reporting of non-serious adverse events (NSAEs). The protocol allowed patients to grade their NSAEs as Mild, Moderate or Severe (that’s right, a severe NSAE) but these grades were conspicuous by their absence in the JPR paper.
It’s worth noting that other protocol changes went in the opposite direction – always relaxing the recovery criteria. Tightening adverse event criteria at the same time, or even post-Lancet, shows not just bad science, but bad faith. As bad as concealing the PI’s involvement with health insurers and the government at entry.
Thank you so much for your assessment, please do continue, there is so much more to be brought to light about the PACE trial.
I’m all ears!
Worth the read, and for people like me that is saying a lot.
Please, please follow up with insights into the disappearance of objective measures.
Yes, please do continue! This is fabulous! Thank you!
CBT and GET were among the first therapies tried on my son. CBT did nothing. GET made him worse. At the time we thought his disease was just getting worse and that exercise would help him to get better. Now that we have become more educated about the disease we can clearly see that exertion worsens the disease and that the GET helped to destroy him. He says he could feel it happening.
When experience conflicts with “science” it’s time to take a fresh look at the “science”.
Thank you, again.
Thank you so much! Please, keep going.
Great Article. Posted in VOAT.
Thanks so much. It’s very heartening to see such a robust critique of PACE trial weaknesses from such an experienced academic. Please, please do continue.
I haven’t finished reading yet, but one comment before I forget. The investigators hypothesized that SMT and APT arms caught up with GET and CBT due to the SMT and APT patients receiving CBT and/or GET after the trial.
But their own data on page 4 in the supplementary materials disproves that hypothesis. They have broken down mean CFQ (fatigue) and SF36 Physical Functioning scores and changes based on post trial treatment of 0 extra sessions, 1-9 sessions, and 10+ sessions.
I’m not very good with statistics, so maybe I’ve missed something … but it looks like they’re proposing a hypothesis which they know is contradicted by the data which they have gathered.
Oh, and a huge THANK YOU for taking this on!
Great stuff. Looking forward to more of this although I’m sure you do realise that this latest paper is just the late night post-pub sausage butty compared to the earlier gourmet extravaganza of the original PACE Lancet paper.
Hey you’re fully recovered and within normal range. Good luck keeping up with those 75 year olds and congestive heart failure patients (objectively speaking).
Thank you! I am much to sick to write what all I think bout this subject but will say as someone whose had severe CFS for 10 yrs & lost everyone that mattered to me because of this disease, I was so insulted when saw the headline that CBT & exercise was the cure. Some days it takes all the strength & energy I have just to take my medicine or go to the bathroom. 10 yrs ago the belief was that CFS was just “laziness & in your head”. These reports have destroyed 10 yrs of trying to get publics understanding of this hell we have to live in to change. I wish one of these researchers could live just one day in my life, feel what I feel, carry the stigma of lazy & crazy I have to & lose all their family & friends because of this disease & the stigmas these kind of reports slap on our heads. Most people dont read an article, scan the headline & form an opinion, 10 yrs of progress is now gone, thanks PACE you made this nightmare we have to live a joke disorder once again.
Please do continue. This picking apart of methodology in PACE is vital ammunition in discrediting PACE. Sadly the views of PWME regarding PACE are ignored or characterised as a ‘vocal minority’.
Ha, talk about lies, dam lies, and statistics!!
The detailed work of people like you will eventually lead PACE to be held up as an example of how not to conduct a clinical trial, and how not to present the data from the trial.
Always good to read a critical analysis from an academic. It would of course be great if Sarah Knapton were to publish such a response via the Daily Telegraph.
Many thanks for undertaking the scarcely enviable task of unpeeling the rotten onion that is PACE.
It’s difficult not to have grave doubts about the mental and/or moral state of the few desperados who obdurately continue to defend it.
Please keep up the good work.
Thank you very much for this, Dr. Coyne. And yes, please do continue. It would be valuable to see how the objective measures disappeared. A U.S. researcher said that the results on PACE’s 6 minute walk test were so low that if they were potential heart transplant candidates, they would be rejected as unlikely to survive.
Thank you for writing this response to the waste of research money and harm to patients by these unscrupulous people (can’t bring myself to call them researchers).
As a patient I was very pleased to read your analysis. Its obviously of interest to a great many patients. I wonder though how many in science, the medical profession, and related government and industry organizations will be interested? They should be, very much so, but there is a long history of problems with this kind of research being ignored.
I do hope you write a follow-up article.
It is still a mystery to me why a disease that costs the world on the order of a 100 billion dollars per year (projected from estimates in the USA) does not receive more scrutiny, and the science taken more seriously. Anyone with financial interest in outcomes, not just patients, should in theory want to see the most robust science, and should not tolerate science that fails to meet reasonable criteria.
I have long regarded the PACE trial as far below evidence based Gold Standard, due to not being double blinded, the use of a manufactured and irrelevant comparison arm with adaptive pacing, and the heavy reliance of subjective measures in a psychological intervention trial. There is provision within Evidence Based Medicine to downgrade the ranking of trial results due to problems. These alone prevent it being Gold Standard (though this is a nebulous and debatable term), before you even get to effect sizes, statistical and methodological errors, and so on.
I wonder what you think about the PACE trial’s papers from an evidence based perspective?
It is sadly absolutely impossible to conduct a double blinded study of psychological interventions, however much we might want to. That of course, if anything makes it more important to make the RCT as perfect as possible in other ways.
Thank you for this article! It finally explained the study for me! Would you consider making a shorter, simpler version for ME patient who tire easily or have trouble reading? (And maybe go through this article, and fix the mistakes in spelling and grammar?)
I couldn’t read this whole thing nor understand what I woulda before either. Having someone like this doctor fighting with the words, understanding & strength us patients dont have anymore, maybe there is one person that actually cares about us now. “ME/CFS, the disease that forces you to exist in a life that isn’t yours because dont have the strength for suicide”…..
Thank you, James Coyne.
In terms of methodological critique of PACE, for years patients have been like the citizens pointing at the emperor and shouting, “He’s got no clothes on!” and the people whose job it was to look out for naked emperors have been shouting, “Shut up, stupid patients! He’s wearing a lovely suit!”
But now you, a fully dressed emperor, are shouting along with us.
Why do the PACE authors keep getting away with publishing their appalling bad science in leading journals such as The Lancet, Lancet Psychiatry and Psychological Medicine (seriously – I’d like your opinion)?
Is it that at £5m, PACE is too big to fail?
What can we do to get this nonsense corrected or retracted?
I’m beyond thrilled that you’ve taken the time and trouble to write this post. I hope you might be planning to write to Lancet Psychiatry.
I’m waiting in eager anticipation of your next instalment.
Thank you so much! Please do write about objective measures. It is my FOI request on 6mwt (6 minute walking test) that ultimately failed as discussed by David Tuller. Happy to be contacted if it helps
Thank you so much for getting involved Prof Coyne.
You have certainly generated considerable interest in and momentum towards getting this dreadful study re-examined.
It would be great if you would do a further piece examining how it was that Dr Anna Wood’s politely and respectfully worded freedom of information requests were determined as being vexatious, both by QMUL and the Information Commissioner. She did a great service to the M.E. patient community by her efforts, which deserved a fair hearing by the authorities which rejected them.
I feel sure that getting access to the PACE trial raw data would be a step closer to exposing the truth.
https://www.whatdotheyknow.com/user/anna_sheridan_2
(Should have added the request was in my maiden name Anna Sheridan)
Thank you very much for this detailed review, and if there is more to write it is highly appreciated. E.g. I have been wondering about the recruitment criterias recruting the patients into the pace study. Would not that be essential for the basic data hence the results?
I’d like ve to see more! I took statistics classes from Helene Kraemer while getting my PhD in Psychology at Stanford. She’s the BEST! So good to see your detailed analysis. Thank you!
Thank you very much for writing this. It is greatly appreciated and I do hope you will continue
Yes please do James!
This was amazing, seriously.
Any chance of getting the gist of this in the telegraph?
Thank you so much for this thorough debunking of the hype surrounding what is essentially a null result.
I very much hope you will continue … I suspect there will be a LOT of interest in you doing so. (though perhaps not from the PACE authors) 😉
If you do write a piece on the objective measures you might be interested to know one of the “disappeared” objective measures – “fitness”(step test) turned up in a tiny graph in one of the follow-up papers. It showed GET and CBT as having the WORST outcomes of the four arms:
http://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(14)00069-8/fulltext
graph alone here:
http://forums.phoenixrising.me/index.php?attachments/chalder2015-fitness-and-legend-jpg.12005/
an FOI request for the data this graph was based on was turned down
Fantastic article. Please continue with the original trial!
I don’t have the energy to read and digest your entire blog, but I get the gist of it – thank you so much! CFS/ME patients have been kicked to the curb and abandoned by the medical profession and it is beyond heartening to have someone like you in our corner – please keep it up! You don’t know how many lives you will touch. 🙂
Thank you for doing this. As someone with ME/CFS, I struggle to process information. I used to analyse complex information for a living so is incredibly hard to feel so diminished. It’s helpful to see the research analysed in a way I can understand.
I don’t know what causes ME/CFS, but I can see this research doesn’t stand up to scrutiny. That’s such a waste when people are so ill. I know there is appetite for more so please do continue!
Please continue! I am very curious what their reasons were for getting rid of all the objective measures…
Thank you for this very comprehensive analysis. I’m very much looking forward to the next instalment. I KNOW there’s going to be one because you’re going to get a LOT of interest and grateful thanks.
What is your opinion of the refusal by the PACE PI, Peter White, to publish the originally planned recovery outcomes specified in the trial protocol, or to release the data to allow the calculation?
I hope you don’t mind me mentioning on your site that #MEAction launched a petition just yesterday. It calls for retraction of misleading claims of “recovery” in the PACE trial that were made in relation to the original Lancet paper and in Psychological Medicine and also requests release of the data / original recovery outcomes. The URL is:
http://my.meaction.net/petitions/pace-trial-needs-review-now
Thanks again.
As of 7:30 pm UK time, there are already
Excellent summary – keep up the good work. The disappearance of the objective measures is a really important issue. Not following patients up afterwards to see if they actually increased activity in any of the groups – esp the CBT and GET groups is a shocker. Other researchers have found that patients reduce activity when encouraged to do more by clinicians. I suspect patients learn that they get worse by being encouraged to do a lot more and moderate their activity downwards going forward. If the nice therapist is not one you want to upset you might just not mention it – so it looks like you’ve ‘improved’ / ‘feel better’ better by subjective measures but this has been achieved by a social learning process and reducing, not increasing activity. This is what I find using pedometers in pwME, FM, MS and other neurological disorders in my clinical practice. Moreover, ‘feeling better’ is quite different from ‘being better’. This gets conflated by those that want to over egg their results. The two are different concepts. The former seems to satisfy psycho-social researchers such as those running the PACE trial whereas what patients want is overwhelmingly the later.
“It’s wrong to say people don’t want to get better, but they get locked into a pattern and their life constricts around what they can do. If you live within your limits that becomes a self-fulfilling prophesy.” Michael Sharpe
One thing that has always puzzled me is how this has been determined. With different operating assumptions, you could see the ability to accept and live within your limits as a life affirming, intelligent, capacity able to reflect and work with your current situation: in other words, a kind of sanity.
Thanks for your work and please continue.
I agree. My attitude towards the ME has always been “Hope for the best but plan for the worst.”
Great analysis. Looking forward tot he next installment.
Thoroughly enjoyed this, please please publish more. I have watched my wife suffer ME for the past 27 years, The physical effects devastated the life of a vibrant wonderful woman but even more devastating has been the mental torment induced by the so called “Wesley school” which seems to have the ear of the UK Dept of Health, Dept of Work & Pensions and some of the British Press. I have always believed there is a financially / politically motivated agenda behind their attitude toward ME/CFS. All of this in spite of the growing mountain of published Biomedical evidence & research, WHO categorisation etc, even statements made by the UK’s Chief Medical Officer. I truly believe that the only hope for ME/CFS sufferers Is that the few with serious credibility, such as your good self, will expose them for what they are.
Please do continue this most reasonable discourse!
Thank you for addressing this issue with clarity, integrity and truthfulness. The whole PACE fiasco has done immeasurable harm to ME/cfs patients and their families in many countries around the world, not just in the UK. We are in need of champions setting the record straight. You are a champion to a very grateful ME/cfs community.
The Chadler fatigue scale could make a interesting study in its own right of how not to design a scale. Not only is it forced the items are non-symmetric in their choices. It has more questions looking at physical fatigue than mental fatigue thus effectively weighting one about the other with no attempt to validate this weighting (as is done with the eq-5d scale). But then weighting is difficult because these aspects are not independent but do not always vary together.
More strange is the use of two marking schemes that do not preserve ordering. With one scheme patient A may appear more fatigued than B but in the other that ordering could flip. This suggests to me that one or the other is not an ordinal scale let alone an interval scale and hence should be treated with huge care in any statistical analysis.
Thank you! I am a retired Head of Maths, with ME, and very critical of the criteria that PACE used to define “recovery” (basically they used the mean and standard deviation to define normality in highly-skewed data), but my statistical skills needed assistance to get a good perspective on their recent claims.
Another ‘please do’ from me too. Much appreciated 🙂
Thank you so much for all this work on this excellent article.ihave experienced the devastation of this illness in my daughter for decades.and have been ill with it myself for 8years also.it has totally devastated our lives and the pace trial was a huge blow.doctors and family members have been completely taken in by it without ever questioning the research..it has led to isolation and terrible hardship for the patients.i can’t thank you enough,to see the truth in your article and in David tuller s article means so much to us all.our deepest heartfelt thanks to you,and if you can keep adding to the truth please do so.huge appreciation for what you have done
Thanks for a great blog, really excellent.
Professor Coyne, thank you so much for this brilliant exposé.
I very much look forward to reading your follow-ups.
If only the original “study”, peer review, and PR had been this thoroughgoing, clear,
and principled. Expect an outpouring of genuine gratitude from the community of patients who have been shouting into the wind about this trial for years.
I would like to add my voice to those calling for more analysis. Thank you for writing this article.
Great blog, thank you. I vote to for you to write another blog please!
The newsletter wasn’t the only priming that took place…
Unlike the APT and SMC groups, the CBT and GET groups were told that the therapies were highly effective and were encouraged to see symptoms as temporary and reversible.
e.g. the patients’ manual for GET says: “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.”
The trial’s GET manual for therapists says: “Participants are encouraged to see symptoms as temporary and reversible, as a result of their current physical weakness, and not as signs of progressive pathology”.
and: “During this programme individuals will learn about the physiological processes that occur in CFS/ME and how exercise can help to counteract and reverse these.”
Whereas the SMC group received no such priming, and the APT participants’ manual says such things as: “The basic underlying concept of adaptive pacing is that a person can adapt to CFS/ME but that there is a limited amount that they can do to change it, other than provide the right conditions for natural recovery.”
Thank you for your very comprehensive summary- it is time for the numerous enormous faults of one of the biggest injustices to humans beings (the PACE trial) be revealed and its history rewritten. Please continue!
Dear Prof Coyne,
Thank you so much for your article and for using your voice in the medical community to speak up on behalf of all of us who are ill with ME. I have been ill for 30 years now, I am now 40. I have been very severely affected, wheelchair bound for many years, bed bound for over ten years. I am using all my strengh today to say a truly heartfelt thanks to you and to ask you to please continue to be so generous with your knowledge and expertise and tell the truth on our behalf. There are so many people like me for whom your words have given heart to tonight and I will go to sleep knowing they’ll reverberate for others outside the ME community too and make a difference for us in the world. The PACE trial robbed many of us of medical help but also of the understanding of our family and friends who believe “science” is always right. Thank you so much and wishing you every blessing .
Thank you for this! Those of us with knowledge of statistics have been beating our heads on the floor for years over the misuse of statistics in these studies – but I’ve never seen ANYBODY dance with the stats like you have here. It’s fantastic. I’m enjoying it greatly – please continue!
Disclaimer – I am not a disinterested party. I have been disabled by M.E. for 20 years, but I live in the US and have been in a number of research studies. Before that, my tests always came back normal, which is business-as-usual for us.
Working with researchers, in 1998 I learned I had a raging infection of HHV-6 Variant A (in a study conducted by the co-discoverer of HHV-6 and its two variants – my viral load was over 3,000, ten times greater than necessary for a diagnosis), and I had abnormal immune biomarkers – the 37kDa Rnase-l defect and a natural killer cell function near zero. On the basis of that information, I started a study with an experimental immune modulator/antiviral, and have improved significantly, going from mostly bedridden in pain and confusion to being able to perform the activities of daily life, drive, read, take walks – a reduced life from having been a professor and mother of two, but a life. i would not have been able to make heads or tails out of your post before I improved on immune and antiviral therapy (heck, when sick, I can’t even figure out how to fasten a seatbelt!)
When I lost the drug for a time (thank you, FDA), I relapsed in less than a year, back to being a bedridden invalid in confusion and pain. Research conducted a year later found HHV-6A and cytomegalovirus active in my spinal fluid, abnormal SPECT scans, very abnormal CPET scores (by that measure alone i would have been considered permanently disabled by the US SSA), abnormal Holter monitor test. There were other viruses active in my blood serum. As one researcher joked, my blood was a toxic stew.
It took a long slow climb back – but first i had to get back on immune and antiviral therapy. Then we very, very slowly started walking again – 6 minutes, then 8 minutes, then 10 minutes – until i could walk 2 miles comfortably. Once again I had a life back. Did I mention that after six months on immune/antiviral therapy the viruses went dormant and the immune biomarkers returned to low normal?
I only write this because this disease is not that mysterious. There are studies now being conducted at Stanford and Columbia Universities using samples from my doctor’s store – one using my spinal fluid was recently published. This one added an abnormal cytokine profile to the other information i had. Similar studies are underway at Griffith University in Australia and very interesting research is coming out of Norway.
Now to be serious. In the US alone there are over 1 million adults with this disease. The best estimate for the UK is 250,000. Demographic research suggests that only one-fourth can still work. Another one-fourth would fall in the severe category – bedridden and/or housebound. In the US, even CDC admits that at least 850,000 victims have no diagnosis. And even though we have some good specialists, there are only a handful of them, too few for the ones who DO have a diagnosis. We must find these people, get them tested, get them treated. I can’t imagine what would have happened to me without my family to take care of me.
The researchers who did my CPET test have also done studies running two-day CPET tests on high-functioning patients (I was not allowed to do it a second day, because my score was so dreadful the first). They were compared to a control set of deconditioned normals (couch potatoes). The scores were the same for both groups on the FIRST day – but on the SECOND, the scores of the ME/CFS (Canadian definition) patients plummeted by as much as half. That research has been replicated in several labs in three different nations. Second-level research includes testing for abnormalities in the blood during the CPET and for specific intervals after.
This was a dramatic rendering of the observation that has historically (going back to 1955) been considered the cardinal characteristic of M.E.: post-exertional worsening of symptoms. Not fatigue. Post-exertional worsening of symptoms. Something blocks our ability to process oxygen and expel carbon dioxide.
I apologize for the long post. I wanted you to know that there ARE alternative views out there – over four thousand refereed-journal articles with biomedical information. The psychiatric literature exists in an alternate universe, self referencing, completely oblivious to the scholarly literature on biomedical evidence.
Most of the very worst patients I have seen are in the UK, and were forced to exercise by the longstanding dogma pushing CBT and GET. Patients were sectioned and forced to exercise. It is horrifying. If there is a strong response to the PACE trial by patients, this is why.
We do not know the cause. We do not know the etiology. But we are making great strides in being able to describe what appears to be happening with this disease. We still are way behind in treatments. What helps me may not help someone else, unfortunately – and there is a treatment that is working with some patients that seems to operate on a theory opposite to the one explaining my own treatment – Rituximab, a cancer drug that reduces B cells, is showing promise in a very carefully constructed study in Norway. Perhaps we are dealing with subsets. Perhaps it is just too complicated to understand without new discoveries of how the body works.
Thank you for reading this far – and please keep going. I’m fascinated.
Please continue. As someone who has been suffering from ME for several years these pace trials rehashed has just broken my heart. I struggle everyday with people who dont believe im ill even medical professionals who refuse to take me seriously. Even though ive been officially diagnosed by the ME centre at Seacroft hospital leeds. I suffer from infections all the time… even as i type im on more antibiotics for ear throat infection. What you have written (even though i read it in bits /sections) gives me hope that not all health professionals are as dismissive. Xxx thank you for that!!!
This morning I have sent your excellent analysis to clinicians and colleagues some of whom teach methodology and critical thinking (as I used to prior to becoming home-bound due to this wretched illness). I have suggested that PACE and your analysis of it henceforth be incorporated in teaching material. As I said on Twitter, this is a great lesson for the methodologically challenged on how not to design a research study, interpret statistics and make inflated or flawed knowledge claims. To me, personally, your analysis serves to further underline the shocking lack of research ethics on the part of a hegemonic circle of researchers.
Thank you, I’m flattered.
Thank you Prof Coyne for this clear analysis of the flaws in the interpretation of the follow up of PACE. Inaccurate headlines make those of us with loved ones with this devastating illness angry but only a calm critique of the science,or lack of, will bring about change. I would be very interested in hearing more of your thoughts on this.
“The Discussion further states
‘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.’
This makes unwarranted and self-serving assumptions that treatment choice was mainly driven by the need for further treatment, when decision-making was contaminated by investigative preference, as stated in the newsletter. Note also that CBT is a novel treatment for research participants and more likely to be chosen on the basis of novelty alone in the face of overall modest improvement rates for the trial and lack of improvements in objective measures. Whether or not the investigators designate a limited range of self-report measures as primary, participant decision-making may be driven by other, more objective measures.”
This struck me, too. It also makes the assumption that seeking out further therapy was driven by patient choice. However in the real world outside the trial, CBT and GET are the only two therapies endorsed by the NHS and NICE. There’s no element of choice about that.
Many, if not most UK doctors won’t prescribe any drug interventions for ME/CFS so that’s one option from the trial removed for a start. And adaptive pacing – outside the confines of the PACE trial – is something that tends to be passed on verbally from sufferer to sufferer, or through charity advice leaflets, as common sense advice rather than as an actual expert-led course. So that’s two for two – the only options left that are at all likely to attend sufficient sessions to be considered “adequate” by the trial researchers, are those accessing CBT and GET options. Moreover, if you’re attached to one of the NHS specialist fatigue services, some of the experts attached to those services put a lot of pressure on people to accept CBT and GET courses, very often with the underlying implication that you’ll be dropped from the specialist service if you don’t cooperate, because you’re just not invested in being well again.
Thanks for your excellent observations. Do you know if CBT and GET are even widely available outside the PACE trial in the UK?
Dr. Coyne,
Here in the middle of Wisconsin, USA, CBT & GET aren’t ever a mentioned treatment because there’s still no doctors that believe or take seriously this disease. I was diagnosed by a my family doctor who according to the other doctors around here is “only” a physician assistant. Only treatment thats ever made it possible for me to function enough to barely take care of my daughter since husband left is highest legal dose of dextroamphetamine along with percocet, anti-depressants & non stop antibiotics. I’m not only one around my area that has to live on this drug cocktail in order to not be bedridden. Lazy & crazy is what us in Wisconsin are labeled as by doctors already, thanks to PACE trials thats not gonna change.
I believe they are applied in the Netherlands and Belgium.
There was a report (discussed here http://forums.phoenixrising.me/index.php?threads/2006-audit-of-belgian-cbt-get-rehab-clinics-large-sample.6072/#post-128713 which assesses Belgian treatment centers.
Thank you so much for tackling this awful situation.
CBT and GET are the main and often only “treatments” available for people with CFS and ME from the UK NHS CFS clinics. I am not aware of any other physical disease in the UK that offers CBT and GET as the main or only treatments.
When the UK Government announced in 2003 that they were setting up CFS/ME clinics with 8.5 million patients were over joyed that finally we might get some medical treatment. However, it became apparent quite quickly that this was to be spent on CBT, GET and activity management as the main treatments. Patients were (and still are) disappointed.
Here is an example of a clinic close to me and is typical of those in the UK. As a long term patient (who has done the CBT and GET etc) this offers me nothing in the way of actual physical treatments. I need to go abroad and pay to see a private doctor if I want anything other than CBT and GET.
“Buckinghamshire
Buckinghamshire Chronic Pain and Fatigue Management Service, Rayners Hedge, Croft Road, Aylesbury, Bucks HP21 7RD, tel: 01296 393319.
[Clinical lead: Dr John Pimm, consultant clinical psychologist.. Interdisciplinary service offering cognitive behaviour therapy, graded exercise therapy and self-management programmes looking at physical, practical and psychological strategies for managing ME/CFS. The service has been running for 10 years. The team is in the process of setting up an in-patient service for people with moderate to severe symptoms. Referrals need to come through a medical practitioner or allied health professional e.g. GPs, hospital consultants, physiotherapists. If people live outside the area then out-of-area funding needs to be applied for.”
http://www.meassociation.org.uk/2007/07/nhs-specialist-services-throughout-the-uk/
In the UK, yes, there is a whole network of “fatigue” clinics offering these services.
The ME association recently conducted a large-scale survey of patients’ experiences with CBT, GET and pacing:
http://www.meassociation.org.uk/wp-content/uploads/2015-ME-Association-Illness-Management-Report-No-decisions-about-me-without-me-30.05.15.pdf
Dr. Charles Shephard at the MEassociation would likely have a good idea of exactly what services are available in the UK.
Outside the UK it seems to really vary depending on country. The main effects of PACE nearly everywhere (even where CFS-specific GET and CBT are not offered) seem to be:
1) that the PACE trial is used as “proof” that ME and CFS are psychosomatic or at least partly based on “faulty beliefs” – leading to diagnostic overshadowing and denial of care, denial of benefits/insurance claims, mistreatment by doctors, etc
2) that patients who turn down CBT and/or GET are viewed as “not wanting to get better” by insurers, doctors, family, friends etc
3) That these form the basis for policy in many countries as the “only evidence-based” treatments, meaning patients often cannot access off-label medications or even symptomatic treatment ( there are reasonably effective medicines for things like POTS, NMH, pain, sleep etc. ) unless they happen to live near and can afford a reputable ME-knowledgable clinician
I’m not sure where to point you for “official” evidence of those last three points, but the internet is riddled with thousands of anecdotal reports of all of the above (blogs, message boards, support groups etc)
Yes, the influence promoting these “therapies” has spread far and wide, even in countries not having specialized CFS/ME clinics as in the UK. In the US, CBT and GET were promoted on the CDC’s Website in their Toolkit for CFS and in their CME courses for health care professionals. Their website also contained reference links back to these UK psychiatrists This is what US physicians relied upon for their “knowledge” about this disease, resulting in it being viewed and dismissed as a psychological problem. This view of ME/CFS had become so ingrained in the medical professions and the general pubic that patients faced much skepticism, disbelief and rejection due to their having a very serious, biomedical disease that was not viewed as such. Many complaints over many years about this were made via both oral and written testimony by patients at the Chronic Fatigue Syndrome Advisory Committee meetings held twice a year to advise the Department of Health and Human Services. Patients asked repeatedly for the Toolkit to be removed and the CDC website revised. It was only after the release of the IOM and P2P reports that the CDC’s Toolkit on CFS was archived.
CBT and GET are also available and strongly recommended for sufferers in Australia, eg: http://www.fatiguecentre.com.au/#/treatment
More worryingly, the research from the Wessley school has been used in countries like Denmark to justify detaining people with ME/CFS in institutions in order to force CBT and GET upon them. For example, Karina Hansen has been locked up by psychiatrists at The Research Clinic for Functional Disorders and Psychosomatics since 2013.
Apparently her health has significantly deteriorated while in their ‘care’ and has now been moved to a facility for the brain damaged. More information here:
http://justiceforkarina.webs.com/
http://www.investinme.org/IIME-Newslet-1402%20Karina%20Hansen.htm
https://www.facebook.com/JusticeForKarinaHansen
I live in Western Australia and have just found information about Graded Exercise Therapy on “The Royal Australian College of General Practitioners” website that was published in March 2015. I am concerned that the PACE study has already influenced Australian Doctors when the science behind it does not appear to be holding up. Although GET or CBT have never been formally recommended to me as a treatment program, getting more exercise has. Knowing that there is such conflicting scientific views about whether exercise is beneficial or detrimental affects my ability to make confident decisions about movement.
Dr Coyne please continue these discussions.
Hi,
First of all congratulations with your fantastic work exposing this false research.
I am a Belgian ME/cfs patient. The use of CBT in combination with GET has been the primary “treatment” in Belgium since 2006. About every two years the organizing university hospitals had to file a self-report to the financing government. Each time those self reports did not show any meaningfull evidence that CBT/GET was effective. Each time the projects were not extended as they were not providing sufficient results compared to the financial input. Each time something very similar was set up to replace the ineffective program.
Fortunatly the 2008 (others are hard to find) repport is in English as we are a trilingual country:
https://kce.fgov.be/nl/publication/report/chronisch-vermoeidheidssyndroom-diagnose-behandeling-en-zorgorganisatie#.VkDo5yv859w
https://kce.fgov.be/sites/default/files/page_documents/d20081027358.pdf
Summarized:
* the patients reported to feel somewhat better on average
* there was no objective measurable improvement in functionality on average
* job uptake declined after “treatment”
What is not or not well mentionned:
* patients to ill were not allowed
* diagnosis is not allways according to strict rules
* patients that dropped out (possibly due to severe drawbacks or fysical inability to continu working out during the treatement) are not counted and dissapear out of statistics.
* I talked to patients that had been said by their medical exam doctor that they HAD to show improvement at their next visit in order to keep getting social wellfare (luckely far from all examiners do that!). As these exam doctors rely on input from unspecified other docters to make their assesment, this may lead to bias in reported improvements towards organisers of GBT/GET therapy. Note also that patient organisations estimate the number of ME/cfs patients that do not receive any social wellfare for various reasons at 50% so patients feel the pressure to not lose their last resource of income.
The situation in the Netherlands is quite similar (same language community).
I personnaly went from being able to live somewhat indepently with some help to homebound ever since I got this wonderfull treatment.
This offical endorsment of CBT/GET as “therapy” is largly influenced by the work of Wesley and co. The PACE follow-up is being posted on a “Health and Science” website from a government linked organisation that called CEBAM that advises health care professionals on Evidance Based Therapy “after researching all available material following strict criteria. I have to admit they have some sidenotes telling basicly “although this is realy Evidence Based and trustworhty there may be some issues with it”:
http://www.gezondheidenwetenschap.be/gezondheidsnieuws-onder-de-loep/verbetert-positief-denken-en-bewegen-de-klachten-bij-cvs
So helpful, thank you so much. I have sent this to James Williamson, a consultant in emergency medicine at Warrington Hospital who thinks we should be grateful for the existence of the PACE trial…grrrrr
If you add your comments to mine (from 2004 onwards), you get some very strong arguments to support the view that this trial was deeply flawed. I keep wondering why no colleague has looked at the means for fatigue and PF and noted that they were all below normal. We have no data for benefits and return to pre-morbid lifestyles, let alone actigraphy to confirm fidelity to the protocol (in other RCTS, only 7 individuals were found to have significantly increased activity levels). IOW, if GET helps, it’s not because people increased their activity levels. When this was studied, it was found that the participants simply reprioritised their activities and paced themselves better. That’s one point for pacing. (Not APT which is as irrational as GET). Also worth looking at the rationale underpinning GET, i.e. positive reinforcement and conditioning theories. Hence people have to stick to predetermined plans of rest and ignore symptoms that are ‘normal’. I have no evidence that any of the subjects had ME as I defined it. The Oxford criteria would remove anyone with neurological symptoms. And their ‘London criteria’ were incomplete and basically rubbish. The % of those with psych disorders is awfully high. how can you determine if your fatigue is worse by judging whether it was worse than two weeks ago, given CFs is chronic and fluctuates? Any fluctuation might reflect the disease, not the treatment. We could write a book.
I’ve been listing the arguments for years but this is rarely taken up. Is it because I is a girlie scientist? surely not! (Half a joke.)
Thank you Dr. Goudsmit. Could you provide links to interested readers for your previous statements? Best.
To add to Dr. Goudsmit’s discussion on the criteria used for patient selection and the issues with the London criteria… PACE also characterized patients according to the CDC 2003 CFS criteria. But they changed the definition to only require symptoms for 1 week instead of 6 months as required by the criteria. The recovery paper acknowledges that this change could result in an inaccurate characterization of patients as meeting this definition.
The PACE authors have made much of the fact that CBT and GET work the same across all these CFS and ME definitions. But given these definitional gymnastics, its impossible to know which of the PACE patients met the CDC CFS or ME definitions and certainly not possible to say that CBT and GET apply to the population of patients that meet ME definitions – given the comments made by Levin.
I am a writer with classic virally triggered ME – I became extremely ill in 1982 after Coxsackie B4 virus. I was diagnosed almost 18 months later by a consultant neurologist. I was only twenty years old. A cluster of people in the west of Scotland became ill at this time. None of us had heard of ME. My initial treatments in the NHS neurology clinic as an inpatient were plasma exchange and immunosuppression. This kind of intervention was possible before what is known the Wessely school took over. This clique of psychiatrists flowered in UK late 80s, early 90s. They effectively tried to ‘disappear’ Ramsay ME (so called after infectious diseases consultant Dr Melvin Ramsay who saw a lot of ME patients) and aggressively pushed a biopsychosocial model of the illness. Who cared if a virus made us ill to begin with, we were perpetuating the illness with false illness beliefs! Claptrap galore which ‘respected’ health editors in UK swallowed like sweeties.The subsequent spin around PACE and the harm it has caused pwME cannot be overstated. There is much on my blog – velogubbed legs – under PACE label for those who wish to know what the unrelenting PACE coverage in UK has been like. If you stood up against PACE, you were a militant and dismissed. I still cannot comprehend how the neuroimmune illness I have had for 33 years was hijacked and distorted to such an extent. It still shocks me.
I’m an ME sufferer who has studied the PACE trial and follow up. This is what I wrote yesterday through tears of rage. (It’s a while since I read the original Pace report, so some of the details below may be a bit inaccurate).
How NOT to design and report a study of ME:
Faulty sample
Design a set of criteria that do not fulfil international criteria for diagnosis of ME.
Recruit patients to your study who fit your own criteria, but do not necessarily fit the international criteria.
Faulty (non valid) choice of what to measure:
Instead of using constantly measuring electronic devices, eg pedometer, to measure patient’s overall levels of activity, use questionnaire (self-reporting) and the distance walked in 6 minutes on a single occasion at the start and end of the study, without taking into account the effect of this walk on the patient’s activity levels before and after (eg post exertional malaise, needing to rest afterwards to compensate for effort expended).
Do not measure in any way the daily or weekly changes in activity levels and symptoms during the 8 months of the study of aftewards for any of the patients.
Faulty methodology
Divide the cohort into 4 groups
group1: Graded exercise therapy (GET) spend 8 months having regular sessions telling patients that they must gradually do more exercise. Do not measure whether they actually do more, or whether they simply compensate for the ‘extra’ they are told to do by decreasing other daily activities.
Group 2: Cognitive Behaviour Therapy (CBT) spend 8 months of regular sessions telling patients that their problem is due to faulty beliefs about their illness, and exercise will not harm them. Again, no measurement of effect on activity levels.
Group 3: Adaptive Pacing Technique (APT) spend 8 months of regular sessions telling patients that they must learn to pace their activities carefully through the day, taking regular rests, so as to reduce the risk of crashes (post exertional malaise). Again, no measurement of effect on activity levels during the study.
Group 4: Symptomatic medical treatment only (SMT) also available to the other groups, ie a sort of control group. Again, no continuous measure of activity or symptoms, sorry to keep repeating myself!
Faulty interpretation of results:
Use the distance walked in 6 minutes on a single occasion at the start and finish of the study as a measure of improvement or otherwise in activity levels,see above.
It would be very surprising if patients who had spent 8 months being told they must exercise more (GET and CBT groups) did not make their best effort to walk further in the 6 minute walk. By not measuring in any way whether these patients relapsed as a result of this extra effort, or reduced activity over the following days to compensate for it, the measure becomes invalid.
Nor would it be surprising it patients who had spent 8 months being advised to pace themselves carefully, or being given no particular advice, but using their own experience of the effects of overdoing activity (APT and SMT) were more circumspect about pushing themselves hard in the 6 minute walk. Again no follow up of the effect of this more careful approach.
Thus even before the study, it should have been able to be predicted that the GET and CBT groups would on average walk further in this test, ie ‘improve’.
Faulty interpretation of results.
Interpret walking further in one 6 minute session as proof of improved health rather than trained temporary increase in effort. Take no account of unmeasured effect on activity levels resulting from that walk over subsequent days.
Similarly the ‘brainwashing’ effect of the GET and CBT programs on questionnaire outcomes should have been expected and allowed for.
Faulty follow-up study methodology
Carry out a study by postal questionnaire 1 to 3 years after the study.
Do not ensure feedback from the 25% of patients who do not respond to this.
Faulty follow up interpretation
Discover that there is now no difference between the groups. Interpret this as a vindication of the GET and CBT approach, because they ‘have maintained their improvement’, rather than that the difference between groups seen initially was probably a result of poor methodology and ‘brainwashing’.
I could go on….
I do hope you can get wider publicity for your critique.
thank you for your excellent points. I am sure that there will be another round with the PACE investigators and this will be quite useful.
In the walking test, the GET group gained 67 metres in 52 weeks, 35 metres more than the SMC group. The CBT group showed no improvement compared with the SMC group. The distance of 379 metres is similar to that achieved by patients with heart failure, and patients listed for lung transplantation.
http://www.meassociation.org.uk/2013/07/pace-trial-letters-and-reply-journal-of-psychological-medicine-august-2013/
I do not understand how the PACE trial authors have not been investigated for fraud and misconduct.
Thank you for this invaluable information. Please keep it coming.
My friend made a nice graph of this:
http://evaluatingpace.phoenixrising.me/sixminwalk.html
Thanks for writing such an eloquent review and putting it on your blog where it would be noticed. Despite our best efforts, we’ve more or less been talking to an echo chamber until David and you. (Though the US government is slowly backing away from CBT/GET, but needs more work, as this protocol is still lauded as being “evidence based” in some important reviews, such as AHRQ and Cochrane. And remains the recommended treatment protocol in every health encyclopedia, and from nearly every health authority that speaks English and most non-English health authorities I hear reports from elsewhere.)
Best,
Janelle
My friend made a nice graph of this:
http://evaluatingpace.phoenixrising.me/sixminwalk.html
Thanks for writing such an eloquent review and putting it on your blog where it would be noticed.
Best,
Janelle
Dear Dr Coyne,
I am impressed by the rapidity, comprehensiveness and clarity of your critique. SImilar thoughts struggled to go through my mind but it would have taken a week to enunciate them half as clearly.
The problems of the PACE study are not a new issue but there is something almost surreal about this new paper. For PACE there was at least a prima facie case for CBT and GET having an effect. The problem was that the methodology was inadequate. In this new study there is no prima facie case for any effect at all. Yet the authors appear to feel they are still justified in interpreting it as if there was. And commentators in respectable journals appear to have swallowed this.
For me the bottom line is that PACE falls at the first fence because of the combination of lack of blinding and subjective endpoint. At least one psychiatrist close to PACE who contacted me appeared not to understand why it is the combination that is important. Clearly, this is because blinding is specifically designed to prevent the bias that arises with subjectivity – which means that you do not need it if the end point is objective, and you do not need objectivity if there is blinding. And the reason why it is universally accepted that trials have to follow these rules is that one cannot rely on scientists not to succumb to psychological pressures to guild the lily. With the initial PACE paper it was just about possible to consider that the authors might be immune to such human failings. With the follow-up study this ceases to be an option. If you can interpret a non-effect as an effect then I think the benefit of the doubt has to be forfeited.
I often think that I can no longer be surprised by the human capacity for lack of insight into ones own thinking (something familiar to psychiatrists?). But it proves not to be the case.
Yours sincerely,
Jonathan CW Edwards
UCL
http://imgur.com/6JfLhRD
First design an open-label trial, without a placebo control arm, that uses subjective primary measures. Then take a year persuading two groups of people (CBT/GET) that they aren’t really ill, that their symptoms are simply a distraction, and that they can do more than they think that they can. And then compare those groups with another group (APT) who you’ve spent a year training to believe that their illness can’t be directly ameliorated by the therapy that they are receiving. At the end of the year, ask each group how they feel. Ta Dah! You have a successful treatment. Oh, unless you look at objective measures, which show no useful clinical differences between groups. But we’ll bury any inconvenient outcomes, and try our hardest to discredit all the objective measures used in the trial.
That’s unfair.
Thank you so much for putting so much thought and effort into writing this! It is greatly appreciated, and I do hope you’ll write more.
Thank you Dr Coyne. Really good analysis. Patients have known for some time that the PACE trial is a very poor piece of work, but you have raised a number of new and interesting observations and done so very eloquently. All the while the media and the medical research community only reads misleading headlines and author’s press release comments without actually reading the paper itself and questioning where questions should be asked, we patients have remained frustrated, waiting for people like you to come and take an honest look at it. PACE cannot survive forever as it is so full of holes that eventually the inevitable will happen, I am grateful that you have spoken out about it though, we need more people like you who’s opinions carry weight with their colleagues.
A fundamental problem with PACE trial is also that it is based on the idea that patients hold beliefs about the nature of their condition that are false and damaging. The authors simply assert this without justification (as far as I can see). The PACE trial relies heavily on subjective outcomes, but if the patients are unable to correctly judge their condition to the point of disability, how could anyone place trust in what they say? The design is fundamentally flawed from the start.
It’s also worth mentioning that subjective outcomes improved much more than the somewhat more objective ones (with patients still being disabled), which contradicts the hypothesis that correcting false beliefs would lead to normal functioning.
Quite so, Professor White said in his reply to Dave Tuller:
“We chose (subjective) self-ratings as the primary outcomes, since we considered
that the patients themselves were the best people to determine their own state
of health.”
http://www.virology.ws/2015/10/30/pace-trial-investigators-respond-to-david-tuller/#comments
Yet PACE is based on the premise that the disease is perpetuated by patients assumed wrong cognition and assumed fear of exercise!
How did they surmise the point at which patients perceptions become credible and trustworthy, to the extent of being viable as a primary outcome?
Dear Prof Coyne –
Thank you, Sir. You do the patients and carers a great service, for which we are immensely grateful.
You also do the psychiatric/psychological sciences a great service. Like any other reasearchers, the PACE trial investigators (and Lancet Psychiatry) should properly be held to account by their peers, against the highest scientific standards.
The PACE trial’s hypothesis is, sadly, illustrative of the default ‘if we can’t explain it, it must be psychosomatic’ mode of thinking that appears still to plague the psychological sciences, and that should have been long abandoned as lazy at best or magical thinking at worst. And as you and David Tuller have explained, the trial’s method is fatally flawed.
Please keep up the good work.
Thank you again.
Jeremy
Brisbane, Australia
As an ME sufferer, I greatly appreciate your willingness to address the PACE trial’s flaws in this blog. By all means, continue your engagement!
Here are some extracts from the manual that was given to CBT participants 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.
And here are some quotes from the manual given to the GET participants (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.
Thanks for this – even worse than I thought, Blatant propaganda designed to influence patients’ self-reported ‘improvement’.
A question, I think I saw somewhere that the original protocol for the trial which was used to get funding and approval for the trial specified activity meters not the ridiculous 6 minute walk. Am I right or did I dream this. If so, the whole trial was not only flawed, but unethical. Can anyone clarify.
Here, in a response to comments to their “Protocol for the PACE trial” paper, the PACE authors explain why they dropped actigraphy as an outcome measure:
http://www.biomedcentral.com/1471-2377/7/6/comments#306608
Objective outcome measures
Although we originally planned to use actigraphy as an outcome measure, as well as a baseline measure, we decided that a test that required participants to wear an actometer around their ankle for a week was too great a burden at the end of the trial. We will however test baseline actigraphy as a moderator of outcome. No biological measures were sufficiently well established to justify their use as outcomes in the trial.
Prof Coyne, thank you for shining a light onto these important issues. Prior to being struck down by ME/CFS, I was an economist with a promising career in front of me. After being forced to exercise by doctors appointed by my employer, my condition substantially worsened. Cognitive impairment among many other serious symptoms from my illness has meant that I have had to abandon my career of choice.
I was stunned when the Lancet published the original PACE trial because, even with my cognitive issues, I could spot many serious methodological flaws in the study. It has been a long time since I worked in economics, but I like to think that an economic study with as many flaws as PACE would never be published in a prestigious journal (and if it was, it would be rapidly torn to shreds by other economists).
Thank you for your hard work (and to those people with ME/CFS who have continued to fight to get this study withdrawn) and I add my voice to say that I hope that you decide to dissect the original PACE study.
There are no “mistakes” in the PACE trial for the simple reason that the entire enterprise has been, and continues to be, an intentional fraud perpetrated to protect the profits of the Wessely School’s paymasters. Those paymasters are, of course, the disability insurers, as was documented by the UK Parliament’s “Gibson Inquiry”. The final report called for a proper investigation of those conflicts of interest. Nine years later, patients are *still* waiting for an investigation.
The one idea that keeps me alive is a burning desire to see justice done for the patients who have died, and continue to die every day, many by their own hand, as a result of the suffering inflicted on us by Sir Simon and pals. Perhaps a few years in a concrete cage may help Sir Simon understand what it is like to be a prisoner of this disease and the uncaring society that has kicked us to the curb.
Thank you and please continue, a plea from someone who is still battling with M.E after 30 years, and has no energy left to fight . My heart sank on the newspaper’s reporting on the PACE trial ,but we sufferers knew instantly the truth that there must be something incorrect in the investigators report .l need help , like thousands of M.E sufferers for someone to challenge the protocol followed and statistics etc etc to this trial..thank you again.
Outside of the obvious thank you! Did you ever imagine you’d fall down this kind of rabbit hole? Nobody takes anything we say seriously, and virtually all of the criticism mustered up by patients and advocates has been completely dismissed, usually in a rather insulting manner. Most of us are not scientists, but nevertheless can spot flaws when we see them–but the parting implication is that we’re somehow ‘anti-science’ or some such for daring to question the Lancet or this study, which has been referred to as ‘gold standard,’ ‘elegant,’ ‘beautifully designed,’ etc.
There’s so much more to how we’re (mis) treated, it’s difficult to believe it’s even possible. Your efforts, in conjunction with everyone else’s involved, are greatly appreciated.
Already in 2010, Prof. emeritus Malcolm Hooper made a 442 page report, detailing the failings of the Medical Research Council and specifically the PACE trials:
“Magical Medicine. How to make a disease disappear. Background to, consideration of, and quotations from the manuals for the Medical Research Council’s PACE Trial of behavioural interventions for Chronic Fatigue Symdrome / Myalgic Encephalomyelitis together with evidence that such interventions are unlikely to be effective and may even be contraindicated.” http://www.investinme.org/Docu…
Well worth a read!
Here’s the full link to Malcolm Hoopers report: http://www.investinme.org/Documents/Library/magical-medicine.pdf
Yes it is a really excellent source of information and background knowledge on the PACE trial, you’ll find it all there!
Is it? Were all the ‘facts’ true?
I have lodged a complaint to the Independent Press Standards Organisation about the Daily Telegraph headline you quote at the start of your piece. ‘Chronic Fatigue Syndrome sufferers ‘can overcome symptoms of ME with positive thinking and exercise’ Oxford University has found ME is not actually a chronic illness”.
I gave them quotes from the paper in Lancet Psychiatry that show that the headline is actually either a great exaggeration of the Lancet paper, or indeed directly contradicting it. I deliberately did not enter into the debate about the quality (or lack of it) of the Lancet paper. I await their ruling.
Hi, James, Am just so very grateful for this work you and David Tuller are doing. Here’s some more context to PACE and how pwME have been portrayed & misrepresented in UK health media. The almost constant myths and establishment spin is perplexing and damaging. But we have grown used to it.
Simon giving ‘Health in mind and body’ lecture: Audio: 16m 40s: ‘PACE is one of the most beautiful behavioural medicine trials we’ve ever seen’. Link here:
http://www.foundation.org.uk/Events/AudioPdf.aspx?s=1200&f=20110504_Wessely.pdf
On Phoenix forum there’s a useful collation of Simon’s papers to date, in which he and others have pushed the biopsychosocial model since early nineties:
http://forums.phoenixrising.me/index.php?threads/simon-wessely-quotes.21025/
Re. media, in summer 2011, there was a veritable month long soap opera of reports in UK press/radio on the alleged threats received by ME/CFS researchers from a ‘tiny, tiny minority’ of pwME. Simon was simply everywhere, telling his story. We were bombarded with sensationalist ME patient as terrorist stories. No one would of course *ever* condone ugly threats, but the media ratcheted the story up, it was utterly bizarre, & harmful to reputations of patients.
http://velo-gubbed-legs.blogspot.co.uk/2011/09/threats-stunning-new-thriller-from-uk.html
We were accused as a patient population of being ungrateful for the (psychological) research being done. Discussion threads were also full of comments from people suffering from mental illness telling us that we were stigmatising mental health by refusing to accept that we had a psychological component to our illness. We were painted as the ME lobby, the ME brigade, the ME militants, the dreadful ingrates, when in fact we have a poorly understood, devastating neuroimmune illness that we just want respected and treated like any other physical illness. We do not of course seek to stigmatise mental illness, or say it is less real, but that is another myth we are routinely whipped with.
You will find that in all of this biopsychosocial bluster/hyperbole in media there is seldom much articulation of how lives are shattered beyond repair by ME. The people who are actually ill are not at the centre of the narrative. And the actual biomedical science is suppressed.
And then in 2012 Simon was awarded the inaugural Maddox medal by Sense About Science, for his bravery in standing up to these so-called ME militants while pursuing scientific research.
http://www.senseaboutscience.org/pages/2012-maddox-prize.html
It was just another slap in the face for ME sufferers, and vociferously opposed by some doctors: http://www.meassociation.org.uk/2012/11/me-bitterest-row-yet-in-a-long-saga-independent-on-sunday-25-november-2012/
I mentioned the late Dr Melvin Ramsay in my first comment, I do wish you could read his slim book, ‘ME and Postviral fatigue states: The saga of Royal Free disease’ (1986). It describes outbreaks of ME around the world since 1940s and is invaluable in understanding the politics behind this illness. And my former consultant neurologist, now retired, wrote the preface. The abnormal muscle biopsies he found in Scottish ME patients in 1980s are also mentioned, I was one such patient. The book is available from ME Association, but I also have a spare copy I would be most happy to send you. Thank you, NASIM
Thanks to PACE 99 percent of doctors and official healthcare in Germany think ME/CFS is a psychological illness which needs GET/CBT to be fixed. Clinical guidelines only recommend GET/CBT as “treatments”. PACE ist rated as evidence based. I am very glad and thankful you took the time to prove otherwise. The fiasco of PACE needs to end for the sake of patients.
Sadly, almost everybody in the healthcare system seems to has been eager to believe in PACE without questioning it. With your and Tullers articles there is hope this might change – thank you!!!
A participant in the CBT/APT arm of this trial, having walked in with a stick, still working and moderate M.E. I exited and collapsed 3 days later at the end of 2011. I’ve been 80% housebound and periodically bed bound since then. Please do continue, I’m eager to find out how this has helped me.
fascinating analysis, excellent article Prof Coyne, the PACE study seems terribly bad science! Good to see people speaking out about it
Thank you for all your efforts. The PACE trial and resultant UK NICE guidelines have their tentacles far and wide. In Ireland, these guidelines are also referenced in our health service. As a result in 2012, my then 12 yr old, who had ME for six months at that time was referred for physiotherapy. It completely flattened him. Six months after that it was suggested that he might benefit from Prozac even though he had no evidence of any depression and this was noted in his file. When challenged, the psychiatrist he had been referred to had to admit that it wouldn’t help any of the symptoms he was experiencing but she wasn’t ‘happy’ that he wasn’t getting any better! Two years later he is still very ill and hasn’t managed any school. In fact he only manages to leave the house for medical appointments. The rest of the time is spent in a darkened bedroom . So thanks again. This gives me hope that this appalling fraud will finally be exposed for what it is.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495840/ after reading the above link lm confused about the information there regarding the Trial’s main objective. It states ‘to determine which non-drug treatments advocated for CFS worked best. So does that mean the researches had already decided the treatments would work before the Trial? also lm confused about the term , , ‘recovery’ they mention, what is the clear definition of ‘recovery’ that they keep using in Trial.and also the 13% who had ‘recovery before the trial started, hw was they allowed to enter the Trial, as l thought to enter the trial they had to be disabled according to there own definition.
Further where is the evidence of another trial/research that the ‘treatment’ works if the P
ACE trial was to determine only the ‘safest’ treatment, some patients became worse so why was the trial allowed to continue. If it was to ‘determine’ the safest’ treatment’ it could have been as low as l patient being ‘determined’ that they had ‘recovery’ so this would make the trial treatment reported as worked.
but this was not about if it worked, it was to determine which was ‘safest’ So where is the trial the ‘treatment actually works, if this PACE Trial was to determine the ‘safest’ lm totally confused if this is indeed correct, as l feel the PACE Trial then should never have be started in the first place and was unethical. If all these flaws are correct then the Science
Commuinity needs to stand up and be counted as this Trial should never have have been funded in the first place.
Thanks very much from Sweden for your brilliant article. We are lucky to have researchers supporting us, but also doctors totally dismissing ME/CFS due to the PACE study.
If people are interested in learning more about the background to the PACE trial there are some further details in the following document.
http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.htm
thank you Thomas M for the link.Its helped me a lot in trying to understand the PACE Trial, which l don’t understand its full context as lm just a ordinary housewife that has no education on Science matters, l have no understanding of the terminology the Authors use in the Trial but even l in my limited education can see the trial was flawed, was unscientific and has to be challenged for the sake of future good Science Practise and research. J.Elston
Hell, if you think PACE was bad just wait until the SMILE study gets published. It’s testing the Lightning Process, a type of quackery that’s claimed by its creator (who by the way says that he discovered it while using his magical powers to spiritually enter other people’s bodies) to cure every disease known. To do this all it does is tell people that they have to convince themselves that disease is just some kind of mental process and by removing all thoughts that you have it you’ll instantly be cured – the idea is that you don’t have cancer, you were just doing cancer and by holding your arms up in the right way and shouting STOP as soon as you think about doing it you can stop it. The Lightning process is three days of that, having an instructor tell you that all you need to do to be healthy is to deny that you have any symptoms and say that you’re perfectly healthy.
They plan to measure whether this worked with nothing but self-reported symptom surveys. Three days of driving in a message that if you stay sick it’s your own fault and you could stop it by just saying that you have no symptoms, then they get you to fill out a form asking you what your symptoms are like and accept that the results of it will be meaningful. PACE needed to twist all their criteria to pretend they had a positive result, but this one is set up from the start to produce a completely false positive result. I’ve got no doubt that it’ll manage to make it past some UK medical journal’s system of best mate review despite that.
You can see their plan for it here http://www.trialsjournal.com/content/14/1/415/abstract and Tom Kindlon’s response (which of course will be ignored) telling them how bloody useless the study is by design here http://www.trialsjournal.com/content/14/1/415/comments
If that goes through unopposed we’re going to end up with the same sort of media coverage telling people to put up money to go through quackery that’s likely to do even more damage than CBT or GET ever could – they at least generally have some kind of moderation about them, the Lightning process says that even if you’re collapsing you need to keep on pushing on and pretending that nothing’s wrong.
If you’re a fan of tragi-comic farce seeing the UK branches of the Science Media Centre and Sense about Science fawning over someone who literally claims to be magic might be entertaining, but I don’t think that’s worth the damage that this is likely to do.
Thanks, Matthew, for alerting people to the SMILE study. I checked at Wikipedia and it is truly bizarre junk science. There still so much to say about the PACE study, but eventually I’ll get around to the SMILE study. While I no longer have as much confidence in scientific journals based in the UK as I once did, I’m confident that results of the study, if it is ever completed, will make it into a reputable journal.
We don’t know all the details of LP because it’s secret. What we know is from a few patient reports and it is worrying. Apparently patients are instructed to lie about their health when asked, with the justification that this is necessary for the therapy to work. The whole approach seems designed to generate the biggest possible placebo effect (in the sense of false appearance of improvement). I don’t recall the details of the trial design but I’m pretty sure it will not involve any sort of reasonably objective measure that could guard against this sort of bias. I have little doubt that the researchers will report great success and that the press will eat whatever it is fed, which will further reinforce the image of CFS as non-illness.
I also worry about trying this on children. A child in Norway tried to commit suicide after a course of LP because it made him feel like he was reponsible for being sick.
http://translate.google.no/translate?sl=no&tl=en&js=n&prev=_t&hl=no&ie=UTF-8&layout=2&eotf=1&u=http%3A%2F%2Fwww.nrk.no%2Fhelse-forbruk-og-livsstil%2F1.7891470&act=url
Thank you very much for your analysis and taking an interest in this. Very much appreciated. I would like to offer some observations on Safety, Ethics and Informed Consent regarding the PACE trial.
In making the claims the researchers made, aside from the question of bias:
Was the advice given to participants in the trial that “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!” backed up with robust evidence? It would appear that the researchers believed they had complete agency over the cause and effects of ME/CFS. (Thank you for the quote, Sheila).
Were study participants informed of the scientific/medical expert biological explanation for their ill health, for example as described in Canada’s Expert Medical Consensus Panel Guidelines (CEMCPG) on CFS published in Journal of Chronic Fatigue Syndrome Volume 11, Number 1, 2003?
Were study participants made aware of the very serious concerns within the scientific/medical community about the use of CBT and GET and whether it’s application in ME/CFS was consistent with good and safe medical practice? (What is ME? What is CFS? Information for Clinicians and Lawyers, Marshall, Williams and Hooper December 2001). See also concerns raised in the CEMCPG (referenced above) and an overview of the Canadian Consensus Documents (2005).
Were study participants made aware of studies by Friedman in 2002 or a 2005 UK Medical Research Council Neuroethics Report , April 2005: Session 2 (“Altering The Brain”)? Both refer to CBT having been shown to alter brain function. The MRC Report says ‘ Psychological therapies such as CBT have now been shown to alter brain function. These developments may alter our view of individuality.’ They ask ‘ What are the risks of changing personality? Is cognitive enhancement acceptable to society?’ and ‘Psychological treatments also raise a number of issues about consent and coercion. How much information patients should be given about the possible effects of CBT therapy on their brain?’. They noted that ‘further research is needed to determine whether such therapies are reversible or if there are persistent adverse effects’ and that ‘there is already evidence that in certain situations psychotherapy can do harm’.
To my knowledge there is nothing in the published information about the PACE trial that adresses any of these questions and concerns, or indicates they have been considered. If answers to the important ethical and safety issues raised by biomedical expert opinion and in the MRC Report, were not given to participants, were they in a position to give their informed consent?
Your challenge to ‘defenders of the PACE study to cite other precedents for this kind of manipulation of clinical trial participants. What would they think if a drug company had done this for the evaluation of their Medication?’ I think this an equally valid question with regard to safety, ethical and informed consent issues in PACE.
Hope you find this of some interest/use and once again many thanks for your analysis which is very much appreciated. Looking forward to your further analysis of PACE.
“You do not have ME, you may have something called CFS, but even then I do not believe your problems are physical, and I think you are depressed”.
“So it is all in my mind, is it doctor?” says the patient threateningly. The correct answer from our truth telling neurologist would of course be “yes”, followed by a plaintive “but psychiatric disorders really are genuine illnesses”, but by that time the doctor will be addressing an empty room, since the patient may well have left in disgust.
Wessely S. “To tell or not to tell”: The problem of medically unexplained symptoms. In ; Ethical Dilemmas in Neurology (eds Zeman & Emanuel), WB Saunders, 1999, 41-53
As Pantomime of PACE continues I thought I’d add another few lines here. Simon’s Mental Elf article – rich in ship imagery – is just so very silly, it’s baffling, but then everything he does in relation to this illness is baffling.
So. In 20011, ScotPHN published a sensible report recommending that in Scotland the Canadian Criteria be used for diagnosing ME and NICE G/L for CFS.
Long version:
http://www.scotphn.net/projects/previous_projects/care_needs_for_those_experiencing_me_cfs
Short version:
http://www.scotphn.net/pdf/ME-CFS_short_report_-_2011_09_09_Final.pdf
Immediately, of course, Simon was in with a paper, Unity of Opposites, telling us what a bad idea this was, he has tentacles everywhere: http://jnnp.bmj.com/content/85/2/214.full
And this, I just found, is a v good review on Phoenix of Wessely’s response to ScotPHN: http://forums.phoenixrising.me/index.php?threads/criticism-of-ccc-smith-and-wessely-2012-unity-of-opposites.27730/#post-528074
An extract I can’t resist from Phoenix review: ‘Wessely’s career has been built on subjective assessments and on assumptions and presumptions about ME/CFS, which by their very nature are subjective. He has no lab tests or objective evidence to support his own case. In fact, and quite ironically, he strongly discourages lab tests and objective evidence. His obsession with preventing the diagnosis / identification of objective evidence via lab tests and other biological based tests in ME/CFS and Fibromyalgia is his most serious defect and flaw, in a medical and scientific sense. The NICE clinics’ refusal to do necessary lab tests and other hospital tests for this illness being the most obvious example of psychiatric interference in the NICE guidelines on ME/CFS and their operation. Depriving patients of the objective evidence means Mr. Wessely and his ilk can conveniently claim that the objective evidence does not exist / is not there, and this forces a reliance on subjective data which can be viewed and interpreted in many different ways.’
And on we go.
Dr Coyne, please continue your attacks on PACE and the followup papers. HMS Pace has now struck at least four giant icebergs in the form of David Tuller’s analysis, the recent NIH announcement to start intramural research and increase extramural funding, the Rituximab research in Norway, and now your analysis.
As a nearly-bedbound patient, I am finally seeing a few reasons to slog through yet another day of social isolation and dismissal by the medical machine. My personal goal is to stay alive long enough to see the “Wessely School” and their insurance industry handlers called to account in a court of law for the suffering and death of patients caused at least in part by their blatant fraud.
I only have one question for Captain Sir Simon:
How long can you tread water?
Thank you so much Dr. Coyne.
Dear Dr Coyne, Thank you so much, I can’t tell you what it means to have your support. I hope so much that the media take as much notice as they do of the PACE authors and Prof Wessley. We badly need professionals in your field to speak up on our behalf, the voices of us mere patients carry no weight and are in fact represented by them as hostile, unreasonable, a “vocal minority” – but many are too intimidated and/or il to speak. I can see much that doesn’t add up in the PACE trial and generally the beliefs of the “Wessley” school have been detrimental to a large sector of MEsufferers, but they are so powerful here. We make points about the selection criteria being toobroad, the high rate of misdiagnosis in our CFS clinics that has been identified by Newcastle University research group, and the limited efficacy of GET/CBT even by the PACE trial results- but do not have the expertise, nevermind the strength, to engage with the authors. With your help, and hopefully of the other experts thathave criticized PACE, and with the NIH report now behind us, , maybe we can look towards a time when we will not be vilified and disbelieved, but our true efforts recognised. Thank you again.
Thank you Dr Coyne, thank you.
Thank you so much Dr Coyne. I’m looking forward to your part 2.
Please do go on and explicate the elimination of objective markers from the trial once White saw how badly things were going. I have posted on that on FB, with a picture of an activity meter to show the object White claimed would be too onerous for the patients to wear for a post-trial measurement.
You may call the trial flawed: I call it fraudulent.