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Home » Posts » Other health conditions » chronic fatigue syndrome » A PACE-gate or an editorial without perspectives?
A PACE-gate or an editorial without perspectives?
Kjetil Gundro Brurberg
The PACE-trial is a large-scale randomised controlled trial set up to investigate the efficacy of graded exercise therapy (GET) and cognitive behaviour therapy (CBT) for patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Some months ago, the Journal of Health Psychology (JHP) published an editorial that painted an unfavourable picture of the PACE trial. The PACE-authors published a response to the criticism in the same journal, and simultaneously, the JHP-editor invited me to share my view on the ongoing debate by writing a commentary article.
Acknowledging that peer-review and sound debates are important constituents of science, I accepted the invitation, and submitted a commentary article co-authored with Signe Flottorp and Aase Aamland. Our contribution was intended to bring perspectives into the debate, aiming for better understanding and lower levels of conflict. Sadly, JHP decided to reject our contribution, essentially stating our arguments to be well known and erroneous. We consider it disturbing when a closed editorial process is used to label opinions as right or wrong. For such a strategy to work, the process needs to be transparent and unbiased. JHP does not seem to satisfy this standard, and authors who are supportive to the PACE trial and the PACE-trialists may seem selectively rejected.
Despite the negative feedback from the JHP, we consider it important to share our view with a broader audience; hence we have decided to publish the commentary article on the Mental Elf. We aim to bring perspectives into the debate about the PACE trial, and also discuss the usefulness of GET and CBT in a wider context. In brief, the effect estimates associated with GET and CBT seem well documented. Whether individual patients find the expected efficacy to be useful, will to some extent, be a matter of personal preferences. Even though GET and CBT can be useful, however, it is also our view that ongoing research should aim at developing new and more efficient treatment strategies.
This commentary was written in response to an invitation from the Editor of the Journal of Health Psychology, who subsequently decided not to publish it.
A large number of trials have consistently shown that cognitive behaviour therapy (CBT) and graded exercise therapy (GET) may be supportive for patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) (Larun et al, 2016; Price et al, 2008). This observation tells us nothing about the possible or plausible causes of the disease. It is worth noting that the effects of CBT and GET in CFS/ME are similar to those seen among patients with other serious diseases where fatigue is a prominent symptom, e.g. cancer (Furmaniak et al, 2016) and multiple sclerosis (Heine et al, 2015; van den Akker et al, 2016). The benefit of CBT and GET does not imply that we can conclude that cancer, multiple sclerosis or CFS/ME occur for psychological reasons. It is difficult to understand why the benefit of CBT and exercise in patients with cancer and multiple sclerosis seems widely accepted, whereas the usefulness of CBT and GET for patients with CFS/ME remains controversial.
We are researchers and clinicians who think that health personnel should meet all patients, including those with CFS/ME, with respect and empathy, and offer the best available treatment with documented effects. It is commendable that some researchers make an effort and conduct trials to determine which interventions may help. PACE is one of several trials that evaluate the effectiveness of CBT and GET for patients with CFS/ME. In a recent editorial, Dr. Geraghty (2016) issues an emotional verdict against PACE based on, what we consider, a tendentious review of the evidence. Some of his arguments would have wide reaching consequences if accepted, for example the argument that involvement in previous trials should disqualify researchers from designing new and better trials. Other arguments seem to be based on unfortunate allegations and misconceptions, which have already been corrected by the PACE authors (White et al, 2017). We consider the PACE authors' response to be satisfactory, and think it is unnecessary to seek further details; however, we appreciate the opportunity to provide a broader perspective.
Dr. Geraghty begins his editorial citing Simon Wessely: 'Science is not always plain sailing and sometimes the voyage is across an angry sea'. This quote gives an excellent picture of real world science and its challenges. Unfortunately, the rest of the editorial fails to follow up on this opening, and it becomes evident that we read the PACE trial (White et al, 2011) quite differently from Dr. Geraghty (2016). Where he sees dishonesty and fraud, we see a transparent, well-conducted and rigorous trial. After a thorough review, we conclude that the PACE researchers have performed professionally. They have undertaken to make detailed protocols and statistical analysis plans available for the public – an example for other researchers to follow. Transparency highlights any differences between the protocol and the final product, but this does not mean that all changes to the original plan are inappropriate. No matter how much time and resources are allocated to trial planning, challenges will arise and trade-offs are unavoidable. Hence, dedicated readers critically appraising studies can always point out some potential problems, but this is generally not sufficient to label an entire trial invalid nor to accuse the authors for dishonesty. All trials should be appraised according to the same criteria, and all possible shortcomings should be assessed with regard to the likelihood that they lead us to draw erroneous conclusions. In the case of PACE, we consider the conclusions to remain stable.
The positive findings in PACE span across several outcomes. Dr. Geraghty (2016) does not appreciate the consistency of these results, but rather conveys a general criticism against the widespread use of patient reported outcome measures (PROMs). Keeping in mind that CFS/ME is diagnosed based on subjectively reported symptoms, it is not strikingly odd that trials focus on patient reported outcomes. There is also a paucity of reliable objective outcomes for this condition. Even though PACE demonstrates that maximum heart rate or lactate levels remains constant or improves slightly following GET, it is appropriate to ask what it means for the patient. PROMs are often more important to patients than objectively assessed outcomes, and researchers should therefore avoid devaluing PROMs on a general basis. PROMs are increasingly used in areas with a tradition of using more objective outcome (Anker et al, 2014), and they may even have long-term prognostic importance (Norekvål et al, 2010). One would therefore expect some degree of correlation between reliable and valid patient reported outcomes and objectively assessed activity levels, as substantiated by recent validation studies (Mahieu et al, 2016).
The criticism made against the PACE trial primarily refers to the author's definition of improvement and recovery, terms that can be somewhat ambiguous. Chemo- and radiotherapy may cure cancer patients of their cancer, but many patients may struggle with side effects for years. When is it appropriate to say that patients have recovered? When they are cured of cancer, when their health condition allows them to return to work or when they feel as well as they did before they were sick? There is no single correct answer, but one has to be aware of the thresholds when interpreting the results. Retaining this perspective, PACE shows that some patients will improve very much following CBT or GET, and the majority will experience some improvement. Some patients will not experience improvements at all. There is a lack of reliable methods to predict who will respond and who will not. This is unfortunate, but this is by no means unique for CFS/ME, GET and CBT.
It will be a major step forward if researchers succeed in developing alternative treatment strategies that work more efficiently than CBT or GET for some patients, e.g. Rituximab (Fluge et al, 2011). Some opponents claim that it is possible to use existing case definition to predict treatment response, and they often shorten debates by circular arguments like stating that people who are diagnosed with ME and report improvement following CBT or GET must have been misdiagnosed with ME in the first place. There is actually no evidence that existing case criteria for CFS/ME are suitable for this purpose (Brurberg et al, 2014), and the PACE trial contributes important data on the relationship between case definitions and the effectiveness of CBT and GET. Some critics devaluate the findings in PACE because patients were recruited according to the Oxford criteria, forgetting that PACE participants were stratified according to much narrower case definitions similar to the CDC-1994 and London ME criteria (White et al, 2011). The effectiveness of CBT and GET was consistent no matter what case criteria that were used (White et al, 2011).
The take home message from PACE is that patients with CFS/ME are expected to benefit from CBT and GET. These results are consistent across several outcomes within PACE, and across several other independent trials as confirmed by systematic reviews (Larun et al, 2016; Price et al, 2008). An effect seen at an aggregated level does not imply that all patients will experience a benefit. Regardless of the type of disease or the type of treatment it rarely does. In the absence of evidence of efficacy for other interventions, health professionals should offer patients with CFS/ME the opportunity to try CBT or GET. Clinicians should talk with patients about available treatment options, and patients can then decide whether they want to try CBT, GET or other approaches. It is sad that some patients have had bad experiences with GET, but it is important to recognise that other case reports, as well as our own clinical experience, suggest that many patients with CFS/ME benefit from these interventions. To maximise the positive effects and avoid side effect, however, it is important that these interventions are led by health professionals with sufficient expertise and experience.
Peer-review and debate are important constituents of science, but we are concerned that tendentious criticism and allegations as set forth by Dr. Geraghty (2016) are counterproductive and may discourage further research. Patients who could benefit from these treatment strategies, and actually want to try, may also lose the opportunity because they lose the courage to try or because health personnel avoid offering them. It is important that patients, clinicians and researchers continue their efforts to acquire knowledge and improve our understanding of the disease.
Peer-review and debate are important constituents of science.
Anker SD, Agewall S, Borggrefe M, Calvert M et al. (2014) The importance of patient-reported outcomes: a call for their comprehensive integration in cardiovascular clinical trials. European Heart Journal. 35: 2001-9. DOI: 10.1093/eurheartj/ehu205
Brurberg KG, Fønhus MS, Larun L, Flottorp S, Malterud K. (2014) Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open. 4:e003973. DOI: 10.1136/bmjopen-2013-003973.
Fluge Ø, Bruland O, Risa K, Storstein A et al. (2011) Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study. PLoS ONE 6: e26358. DOI:10.1371/journal.pone.0026358
Furmaniak AC, Menig M, Markes MH. (2016) Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database of Systematic Reviews. DOI: 10.1002/14651858.CD005001.pub3
Geraghty KJ. (2016) 'PACE-Gate: When clinical trial evidence meets open data access. Journal of Health Psychology. DOI: 10.1177/1359105316675213
Heine M, van de Port I, Rietberg MB, van Wegen EE, Kwakkel G. (2015) Exercise therapy for fatigue in multiple sclerosis. Cochrane Database of Systematic Reviews. DOI: 10.1002/14651858.CD009956.pub2.
Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. (2017) Exercise therapy for chronic fatigue syndrome. Cochrane Database of Systematic Reviews. DOI: 10.1002/14651858.CD003200.pub6
Mahieu MA, Ahn GE, Chmiel JS, Dunlop DD et al. (2016) Fatigue, patient reported outcomes, and objective measurement of physical activity in systemic lupus erythematosus. Lupus 25:1190-9 DOI: 10.1177/0961203316631632 [PubMed abstract]
Norekvål TM, Fridlund B, Rokne B, Segadal L et al. (2010) Patient reported outcomes as predictors of 10-year survival in women after acute myocardial infarction. Health Quality of Life Outcomes. 8: DOI: 10.1186/1477-7525-8-140.
Price JR, Mitchell E, Tidy E, Hunot V. (2008) Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database of Systematic Reviews. DOI: 10.1002/14651858.CD001027.pub2.
van den Akker LE, Beckerman H, Collette EH et al. (2016) Effectiveness of cognitive behavioral therapy for the treatment of fatigue in patients with multiple sclerosis: A systematic review and meta-analysis. Journal of Psychosomatic Research. 90:33-42. DOI: 10.1016/j.jpsychores.2016.09.002 [PubMed abstract]
White PD, Goldsmith KA, Johnson AL et al. (2011). PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 377:823-36. DOI:10.1016/S0140-6736(11)60096-
White PD, Chalder T, Sharp M et al. (2017) Response to the editorial by Dr Geraghty. Journal of Health Psychology. DOI: 10.1177/1359105316688953
Tagged with: chronic fatigue syndrome, cognitive behavioural therapy, commentary, graded exercise therapy, Journal of Health Psychology, myalgic encephalomyelitis, research methods
Kjetil is a senior researcher at the Norwegian Institute of Public Health and an associate professor at Western Norway University of Applied Sciences. He is a medical physicist with a PhD in tumour physiology and medical imaging, and is now working to promote evidence-based practice by supporting guideline processes, by giving lectures and by authoring systematic reviews. He has co-authored several systematic reviews about chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), e.g. a systematic review about case criteria and a traditional Cochrane review about the efficacy of exercise therapy for patients. He is also co-authoring an upcoming Cochrane review about exercise therapy based on individual patient data, a work that has given detailed insight into the existing evidence.
Keith Geraghty
View July 19, 2017
Dr. Kjetil Gundro Brurberg is currently working with the PACE authors, his group have close links to the PACE team, he is deeply biased. I find this blog offensive, insulting and bordering on propaganda. I think its a slur on open scientific debate and I think Mental Elf should consider whether or not it is being used as a media PR mechanism for the PACE team and their friends.
As an ME/CFS expert working in this area to improve the health and wellbeing of sufferers, I find the suggestion that my work would discourage sufferers from seeking care is offensive. This author needs to consult a paper published just this week by Collin and Crawley in BMC Health Services Research, a paper on outcome data from UK specialist CBT-GET clinics for treating ME/CFS: less than 5% of patients said they no longer had ME/CFS after treatment or at follow-up. Unfortunately, CBT and GET are not cures for ME/CFS, and scientists, like me and others, have a right to scrutinise trials like the PACE trial, even if that is uncomfortable for the author of this blog who writes that GET is beneficial. I will not rehash the PACE trial here, Its a a flawed trial, The Journal of Health Psychology has published a series of papers on the PACE trial from invited commentators, including the PACE team and others they recommended. Overwhelmingly, most commentators agree with the points I raised in my paper "PAGE-GATE" and my follow-up "The PACE Trial: Biased Methods Unreliable Outcomes.
I encourage all Mental Elf Readers to look at these papers for themselves, to look at the wave of criticism that has befallen the PACE trial, not from me, but from international experts and then consider that this blog is written by one of the PACE authors friends.
http://journals.sagepub.com/eprint/iXpCNJk6zd34nFpSy4NK/full
Aaron C replied:
It appears that Dr. Brurberg does not understand much of the PACE criticism, and because of this many of his arguments are nonsensical. Here are two choice disagreements I (and many others) have with him:
"The positive findings in PACE span across several outcomes. Dr. Geraghty (2016) does not appreciate the consistency of these results, but rather conveys a general criticism against the widespread use of patient reported outcome measures (PROMs). Keeping in mind that CFS/ME is diagnosed based on subjectively reported symptoms, it is not strikingly odd that trials focus on patient reported outcomes."
This missed the point entirely. The headline case against PACE is that is an unblinded trial without objective outcome measurements. You can have a valid trial that is unblinded, you can have a valid trial that relies solely on patient reported outcome measurements, but you cannot have a good trial with both qualities because then there is no controlling for the placebo response. The very modest PROM gains seen in the PACE trial, the null results found at the 1-year follow up, all suggest placebo and confirmation bias at work. A new drug trial with just this one flaw would be rejected out-of-hand.
"There is also a paucity of reliable objective outcomes for this condition."
Not true. The PACE trial originally planned to use actometers to measure patient activity. Actometers were used in Dutch studies to do just that, but a 2010 review of all three of them found that "Although CBT effectively reduced fatigue, it did not change the level of physical activity." In other words people said they felt less tired, but they didn't actually engage in more activity. Suggesting again confirmation bias and the placebo response rather than actual efficacy. (https://www.researchgate.net/publication40846607_How_does_cognitive_behaviour_therapy_reduce_fatigue_in_patients_with_chronic_fatigue_syndrome_The_role_of_physical_activity)
In short the PACE trial was poorly designed, poorly implemented, and poorly analyzed. Dr. Brurberg might disagree but he refutes very little of what Dr. Geraghty wrote—and much like the response by White et al, the arguments he does make miss the point. I strongly second Dr. Geraghty's suggestion to Mental Elf readers to look into this more closely before taking Dr. Brurberg at his word.
Anonymous reviewer replied:
There are objective tests e.g. Paul et al 1994, but no one uses them. The fact that it was an unblinded trial is rather irrelevant as you can't do blinded trials on interventions like CBT. However, there are major flaws in PACE and similar trials. The selection of patients is one thing. This leaves researchers free to study people with fatigue due to stress and depression, which respond to a degree to CBT and GET. Just one of the issues we've discussed in the JHP. The authors covered the same arguments as others, which is the main reason why it was rejected.
Patient replied:
As pointed out by Brurberg, the PACE trial stratified patients using various criteria, and over 80% of patients in the trial had PEM.
Peter Trewhitt replied:
Brurberg does not state here that over 80% of subjects in the PACE trial had PEM. My recollection is that this is not possible to say in relation to the original study participants, though others will correct me if I am wrong.
More recent PACE inspired studies have raised the issue of PEM, but many have concerns about how they define it.
> The fact that it was an unblinded trial is rather irrelevant as you can't do blinded trials on interventions like CBT
The original commenter's point is explicitly NOT that unblinded trials are invalid:
> You can have a valid trial that is unblinded, you can have a valid trial that relies solely on patient reported outcome measurements, but you cannot have a good trial with both qualities
James K replied:
I wonder why they are so afraid of post-publication peer review and consistently fail to address the central concern, namely that subjective outcomes are inherently biased in unblinded non-pharmacological trials, just as they are in alternative medicine.
Repeating claims of efficacy when no objective measures of functioning have been shown (and those that did explicitly measure activity levels or neuropsychological testing showed no change between groups) shows that these people simply don't care about truth.
We as patients are telling you (authors and defenders of these trials) that these questionnaire measures like the Chalder Fatigue Scale are irrelevant to our needs. It is not the subjective measures of symptoms on questionnaires that we care about, it is the impact on our lives. You (authors) need to start listening!
Anonymous replied:
View January 9, 2021
This is an incredibly entitled viewpoint. One could easily make the argument that you (patients) need get a degree in medical research and begin performing the studies that you wish to be performed.
Kjetil G. Brurberg replied:
I was invited by the Journal of Health Psychology to comment on their ongoing PACE debate. Realizing that some people might view my role in a Cochrane review based on individual patient data as a potential conflict of interest (COI), I consulted the editor on these issues before accepting the invitation. Shortly thereafter, the editor confirmed that he did not see my potential COI a big problem, and that he still wanted me to write the commentary article. The same COI, however, suddenly became a major issue when I submitted the commentary and my opinions were made known. What happened?
Dr Geraghty seems to operate with a dynamic definition of bias implying that other rules apply to people who share his views. The observation that most JHP commentators agree with the points raised in his PACE-GATE publication is as expected when taking into account that all authors who have been supportive to the PACE-trials have been collectively refused.
Dr Brurberg it is heartening that you persisted in getting this commentary published despite the personal criticisms inherent it its original rejection and it is particularly heartening that you are responding to comments here given the historical reluctance of PACE supporters to engage with disagreement directly.
Whilst, understanding that you are motivated to respond first to the perceived misrepresentation of your conduct around the original submission of this commentary, I sincerely hope you plan to respond to the specific issues of fact relating to PACE in the commentary and the profound concerns about your failure to recognise the PACE methodological failures raised in the comments here.
Robert McMullen replied:
"all authors who have been supportive to the PACE-trials have been collectively refused"
Your statement is not supported by the facts, Dr Brurberg. JHP has published a response to Dr Geraghty's editorial by the PACE authors, and a commentary in defence of PACE by Petrie and Weinman.
http://journals.sagepub.com/doi/full/10.1177/1359105316688953
You covered the same ground as others, and it was decided we'd try and add to the debate, not let people repeat the same thing over and over. Reviewers have to be fair. We were not censoring anyone; just trying to make a contribution to the debate. Something a bit different to move things along. Your paper didn't. You appear to be stuck to a narrative that has major flaws. If people get ill after minimal exertion, then increasing the amount of activity will make them more ill. GET is therefore not appropriate for classic ME or the concept of CFS in the USA. It's only relevant for people with chronic fatigue due to stress or another psychological problem. Why is it that some people can't accept that? Why this obsession with chronic fatigue due to lack of activity, especially when Dutch and American trials have shown no increases in activity to explain any improvement. As a psychologist, this obsession/group think fascinates me. NB no longer involved with the journal.
I think your idea that exercise can't help PEM is itself an unvalidated theory. Friedberg (2002) found that replacing stressful activity with mood-enhancing activities significantly helped one person with CFS, even though daily step count was actually reduced.
Stress has a significant physical effect on the body, so it's certainly plausible that negative stress causes PEM, and that CBT and GET could help (as long as the treatments are not stressful). Studies also show that the majority of CFS patients report abnormal stress in the 6 to 12 months preceding their illness.
Your negative attitude to psychological factors being involved in CFS is well known, so this isn't really surprising.
'Patient' you give one example of someone finding 'mood enhancing' GET helpful, if we are to rely on anecdotal evidence, why is this one anechedote more significant than the hundreds if not thousands of anecdotal reports of GET making the condition worse in the various patient surveys, on the patient forums and indeed in the comments to this post?
I would be interested to see the reference to abnormal stress preceding onset of ME if you have the details. How did they establish links between the occurance of stress and the onset of ME/CFS? How did they establish controls? How many people that do not have ME/CFS if asked would report stress in the last six months? What criteria did they use to define ME/CFS, given many weaker definitions fail to distinguish between chronic fatigue the symptom and ME/CFS? Stress and burnout have some over lap of symptoms, does this study exclude too broad a definition of CFS, does it avoid the common confounding of the symptom of chronic fatigue with Chronic Fatigue Syndrome? What form of onset did the patients display? Obviously with onset associated with an infection, it becomes impossible to distinguish stress as a contributory factor to that infection through a weakened immune system from stress as a supposed contributory cause of ME/CFS. Studies of this form only offer hints, and to provide answers it would be needed to develop a model of stress triggering ME/CFS that would predict specific experiences result in ME/CFS.
Given, as patients with ME we are desperately seeking answers and explanations, often we are attracted to the idea that a period of stress or a stressful event is the original trigger to the condition. This is further supported in many people's minds by the fact that mental activity or psychological stress can as well as physical activity and physical stress can worsen the condition. However, this is not enough to justify asserting a causal link in relation to onset. How do we measure the accuracy of the ME/CFS patient's recall of stress, when they may already be primed to over report stress in an attempt to rationalise their medically poorly understood condition.
If we are allowing anecdotal evidence, my original ME onset, associated with glandular fever occurred when I was doing a demanding and stressful job. After several years I changed jobs, was working part time, moved to the countryside and thought I had recovered completely. However, several years into being 'recovered' and whilst leading a remarkably stress free life, I had a bad dose of influenza and had a major relapse, my ME being significantly more disabling than it had been previously, having to give up work completely. If stress was the cause, why did I get worse following the second infection when stress was no longer a factor in my life.
A major problem in such theories is the variability between patients and within patients. It will probably be possible to find an individual patient that seems to supports any theory at all. Until theories become predictive they have no therapeutic import. So far the PACE based psychosocial models are failing to be predictive. The therapies based on them have no demonstrable effect other than a slight increase in patients perception of how ill they are that does not persist beyond the studies. In contrast some of the biomedical studies are now at the stage where they are able to predict from samples seen blind, not only who has ME/CFS, but also the severity of their condition. We are not far away from non subjective diagnostic tests.
You say that the assertion that PEM, a physiologically measurable adverse response to exertion, should be a contra indicator for GET is an unsupported theory. In relation to the short term this is not true, it is by definition the case that exertion is contra indicated. Over the longer term we have no scientifically reliable evidence that PEM is reduced by increased activity, indeed a very recent study indicated that 95% of patients seen by clinics relying heavily on CBT and GET are left with long term disability after these interventions. Further we have the consistent survey result that the majority of patients report adverse responses to GET.
Also the comments here are arguing against a psychosocial basis of ME, not saying that there is no psychological component. The commenters acknowledge the secondary psychological factors that often occur in major debilitating chronic conditions. This is what is being looked at when cancer or MS patients are given CBT. No one is arguing that such support is not be relevant to ME/CFS, rather that it should not be the primary, indeed often the only intervention available.
Sorry, in my reply above in the sentence "The therapies based on them have no demonstrable effect other than a slight increase in patients perception of how ill they are that does not persist beyond the studies." the word 'ill' should instead be 'well'.
Keith Geraghty replied:
Unless Dr Burnberg has insight of every commentary Prof Marks (editor of JHP) rejected, I cannot understand how he believes only commentaries that agreed with me were permitted. I believe Prof Petrie and Weinmann are colleagues of the PACE authors and had a commentary accepted – so sadly Dr Burnberg's assertions are inaccurate.
Many academics have papers rejected – I have papers rejected monthly; it's part of academic life. You go back to the drawing board and work on your papers to improve them, or you find a journal that might accept your work. What Dr Burnberg has done is write a blog in protest at his rejection in Journal of Health Psychology and he argues his lack of disclosure of conflicts of interests he held, plus those of the reviewers he recommended, were not the reasons he got rejected – when the editor suggests this was the main reason. I tend to accept the editor's version of events.
Unfortunately, Dr Burnberg, your commentary didn't meet the requirements of the journal, or you failed disclose conflicts, which are ethical codes set by the journal. If we all wrote blogs about papers we had rejected, there wouldn't be enough space on the internet.
Ivana Fulli MD replied:
Thanks for pointing out the conflict of interests.
I couldn't help wondering why could explain such a daring at trying to pass for the victim of unfairness after the understandable rejection for an editorial of this mix of confusing reasoning and alternative facts like declaring PACE « a transparent trial » after a huge sum had been spent on legal fees in a failed desperate attempt to not make the data public http://theprintnews.co.uk/2016/10/judge-dismisses-qmuls-appeal-university-must-release-pace-data/
Quite desperate at a time of #AllTrial and #AllData !
The other comments are informative enough but I would like to add that you were smeared unjustly and most shockingly also for being a sufferer yourself.
Quite another bold move considering how politically correct and trendy it has become in GB to get more credential as a researcher, clinician or even data scientist because of one's private struggles with mental health.
You are the real whistle blower in my opinion if there is any to find in that extraordinary story of so many patients and too few brave researchers battling against powerful academics helped by colleagues remaining silent about the many obvious shortcomings of #PACE.
Wisdom would have make the PACE authors and their friends content with the elves having published Sir Pr Simon Wessely 's much more subtle defense of their shortcomings and results.
Anton Mayer (@MECFSquestions)
For outsiders it can be difficult to understand scientific controversy. Why is the PACE trial being criticized?
The PACE trial reported that 22% of chronic fatigue syndrome patients recovered following graded exercise therapy (GET), and 22% following a specialised form of CBT. Only 7% recovered in a control, no-therapy group. These figures were based on a definition of recovery that differed markedly from that specified in the trial protocol.
This new definition of recovery relied on defining "normal physical function" to be close to the average of patients with rheumatoid arthritis.
More about this here:
Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial
http://www.tandfonline.com/doi/abs/10.1080/21641846.2017.1259724?journalCode=rftg20
In fact the PACE trial and other studies claiming positive effects for CBT/GET for chronic fatigue syndrome have many other problems as well. In particular they share the same flaw of trial design relying on subjective outcomes, with a lack of blinding, and a typically inadequate control group. Due to this flaw it's not possible to distinguish treatment effect from nonspecific effect. Outcome switching is also common in the literature. That a large number of trials consistently report an effect can just mean that they all share the same flaws and I think the case is now very strong that this is the most realistic interpretation. Indeed, trials of CBT/GET also consistently show a lack of benefit on more objective outcome measures such as steps per day, employment, receipt of benefit, fitness measured with a step test, and so on.
In March, over a hundred CFS researchers and clinicians signed a letter asking for the retraction of the misleading recovery claims:
An open letter to Psychological Medicine about "recovery" and the PACE trial
http://www.virology.ws/2017/03/13/an-open-letter-to-psychological-medicine-about-recovery-and-the-pace-trial/
S Gregg
Dr Brurburg,
After reading your commentary it seems obvious that the reason it was rejected by the editor of the JHP is because it contributes nothing of value to this important discussion.
Your comments fail to engage in any meaningful sense with the many criticisms that have been made of this trial, choosing instead to simply repeat the platitutes and evasions that the PACE authors always rely on when their work is questioned. Given that the PACE authors themselves had already authored such a reply – and that the JHP contribution by Petrie and Weinman employed the same evasions to cover exactly the same ground – I suspect that the editor of the JHP felt there was no need for the Journal to publish a third article which side-stepped the issues in the exact same fashion.
You were asked to provide a commentary on the contentions surrounding PACE, and you chose instead to try to handwave the entire controversy away with the phrase "We consider the PACE authors' response to be satisfactory, and think it is unnecessary to seek further details" – after a statement like that I think it's completely unsurprising that the JHP felt the rest of your commentary added nothing to the debate and was therefore unworthy of publication.
"Even though PACE demonstrates that maximum heart rate or lactate levels remains constant or improves slightly following GET, "
This is simply not true PACE never measured lactate levels and I believe did not measure heart rate unless it was done as part of the unpublished step test. The step test itself was a secondary outcome which has not been published and hence PACE is not compliant with the CONSORT guidelines.
Comments on PROMs are incredibly naive. PACE was a trial aimed at changing how patents thought and viewed their symptoms and illness and so asking how patients think about they think about their illness is not a methodologically sound thing to do.
Whats more the differences between the subjective and objective outcomes suggest there is considerable bias within the subjective measures. I think entirely predictably.
What is perhaps worrying is that researchers are unaware or not considering such issues. This could mean if they follow a similar path they will produce meaningless work.
That is of course not even getting to the statistical issues around scales and assumptions that you can ask a set of questions and expect the answers to all be equidistant which is made when quoting the mean and SD.
The use of PROMs in PACE with different marking schemes that do not preserve ordering should worry everyone. It is mathematically wrong to quote the mean for such marking schemes as is done with the CFQ
It would be strikingly odd to rely solely on PROMs in an unblinded pharmacological trial, and it is illogical to simply ignore the placebo effect / desire to please the therapist when it is entirely possible to use objective measures to rule those effects out. Example objective measures include actometry, use of healthcare resources and employment measures. The PACE trial decided to drop the first and CBT/GET has failed to show any statistical benefit when assessed using the others.
There is no argument against using PROMs when supported by objective measures, but focusing solely on self-reported measures whilst disregarding contradictory null results on objective measures (or failing to include such measures where possible in the trial design) is scientifically indefensible in an unblinded trial. The claims of efficacy based self-report and no blinding is a hallmark of alternative medicine, not reliable medical science.
The discussion on CBT is poor and naive. CBT is really a delivery mechanism aimed at changing cognitions (i.e. beliefs). The question in doing a comparison is what beliefs are being changed. So CBT may be helpful for people by changing negative thoughts around being ill and help them cope that way. But CBT for PACE was not doing that. It was basically an illness aversion therapy that told people if they changed their illness beliefs they will recover.
So CBT should be thought of as a delivery mechanism and discussion should include thoughts on the payload. Otherwise its like saying injections help people with cancer so injecting other people with other things will also work.
Adam Lowe replied:
I think patient frustration with trials like PACE is that they don't really want to get to grips with underlying pathology, but rather focus on maintaining a baseline of chronic illness that doesn't really lead to recovery. That money continues to be spent on CBT and GET, which don't show any real success, also means money is diverted from studies into the underlying pathology which could, in theory, show much stronger recovery rates.
The cancer and MS analogies are often made, but there's a key difference: no one with cancer is *just* given CBT and GET. These are treatments for secondary consequences of the illness, and usually prescribed after other treatments have dealt with the core problem. The underlying pathology is usually dealt with first. Would you really forego chemotherapy or radiotherapy, for example, for GET and CBT? No, you wouldn't. And yet, these two treatments are the primary (and usually only) treatments offered to ME/CFS patients, due in no small part to the undue influence exerted over this area of medicine by the PACE trial and its supporters. There will continue to be a lack of treatments if we continue to waste time on trials we already understand (and which don't really show success anyway).
We should be looking at root causes, such as viral, autoimmune or metabolic markers, and then finding ways to address these problems. It's no surprise anti-virals like vacyclovir and imunovir work in some, and autoimmune disrupting medications like LDN work in others, when an ongoing study funded by the NIH seems to have identified three subgroups that display viral, autoimmune and, possibly, metabolic issues underlying three major subgroups. If we instead focused on those research leads, instead of wasting time trying to promote PACE, we might have a much happier patient population. (Early results on subgroups: http://www.prohealth.com/library/showarticle.cfm?libid=30555)
We seem to be going round in circles and funding the same problematic treatments. Let's move on and actually try to fix this illness.
Nasim Marie Jafry replied:
I would add that people with cancer or MS or lupus are not told they have false illness beliefs. PACE supporters are simply disingenuous to suggest that CBT is being used as secondary supportive therapy for ME, it has always been a therapy to retrain patients' 'faulty thinking'. That is how the Wessely-influenced PACE team operates. And graded exercise therapy (GET) is actively harming ME suffererers. Shame on all those who are continuing to deny the reality of the harms visited on ME patients by GET and CBT. Beggars belief. PACE is dead in water. Move on, please, and actually give science a chance to help those whose lives are blighted by this hellish illness.
There are some important aspects concerning trials of exercise for CFS, in the form of GET, or otherwise.
A study of CFS patients following a graded exercise program while wearing accelerometers showed that initially patients were able to gradually increase their activity levels, but after several days their activity levels declined. The control group did not develop exercise intollerance.
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280928/
Several other studies have found that CFS patients objectively exhibit an unusual response to exertion on a variety of metabolic, neurologic and immunologic parameters. The effect is a decline in fitness and worsening of symptoms which is not observed in sedentary controls. This phenomenon has been called "post-exertional malaise", or PEM. The US Institute of Medicine published a review of the literature on CFS and felt that the evidence for PEM was strong enough to refer to the condition as "systemic exertion intollerance disease".
Source: http://www.nationalacademies.org/hmd/Reports/2015/ME-CFS.aspx
On one hand we have a dozen or more studies showing objective evidence that patients tend to decline with exertion rather than improve as would normally be expected. On the other hand we have the PACE trial which claims that graded exercise therapy is effect. The PACE trial has no objective data in support of this claim, and even removed objective measure of steps per day from its protocol while the study was underway. The PACE trial contained a fitness and a walking test, and neither showed any clinically significant improvement. In fact, on the walking test patients had scores similar to patients with major diseases such as multiple sclerosis and heart failure. Since in PACE daily activity levels were not measured, we cannot be sure that patients were actually receiving the exercise dose in the intended quantity (patients may reduce other activities in order to stick to the GET program).
*It is difficult to understand why the benefit of CBT and exercise in patients with cancer and multiple sclerosis seems widely accepted, whereas the usefulness of CBT and GET for patients with CFS/ME remains controversial.*
Perhaps it would be helpful for the authors of this piece to go back to the very basics of M.E and to understand that the cardinal symptom of the illness is that any exertion brings about a crash in this illness. Exertion can mean sitting up or brushing teeth for a severe sufferer. For a mild sufferer, it might mean going for a walk or attempting to engage in any exercise which leads to a rise in heart rate. For many other illnesses which involve fatigue, gentle exercise relieves symptoms. It is therefore redundant to make any comparison between them. Post-exertional malaise is something which can be tested for objectively (see Van Ness). It has been written about extensively by sufferers. And yet those supporting the PACE authors don't seem to be able to understand its importance or severity. At worst, there are many cases where GET has caused harm to sufferers, in the worst cases pushing people from being moderately affected to being severely ill. This can mean the patient becomes bedbound, unable to tolerate light or touch and needing tube feeding. The risks associated with GET are not minor.
*The criticism made against the PACE trial primarily refers to the author's definition of improvement and recovery, terms that can be somewhat ambiguous. Chemo- and radiotherapy may cure cancer patients of their cancer, but many patients may struggle with side effects for years*
Let's not be disingenuous here. If chemotherapy leaves a patient in remission, they are in remission. It is entirely regrettable that someone may be left living with side-effects of the treatment but that is a secondary issue. The fact remains that if you have a tumour which threatens your life one day and six months post treatment you don't, then you are 'cured' (is the word cure actually appropriate with cancer?). I am sure that to most patients, surviving their cancer and living with side effects is infinitely preferable to dying of cancer. Many still have excellent quality of life, being able to leave the house, work, be active parents to their children and exercise. The 'cure' is tangible in that they are no longer at risk of death and a malignancy is no longer spreading or doing damage to their vital organs/bones. Medicine isn't perfect but the millions invested into cancer research over the years have increased survival rates dramatically. Ask a breast cancer patient if they'd rather have the disease now or go back 50 years ago and experience having it then. They will be able to find many objective reasons as to why it's preferable to have it now.
Under the terms of PACE, you could as a sufferer be considered cured if you got worse than when you entered the trial. It is the most glaring problem possible. You could have come out of it considerably less physically able than a fairly frail elderly adult and still be considered cured. Is that the equivalent of treatment leaving no discernible signs of cancer in one's body? I would strongly argue that it is not. Being cured of M.E might mean something different to different sufferers. To me it would mean no longer suffering post-exertional malaise. Not experiencing crushing exhaustion after something simple like having a conversation. Having the energy to get through the day without needing to lie down or needing help to feed myself or keep clean or leave the house. I am quite comfortable accepting that even with a lot of research, science might only be able to offer me some improvement and not a complete cure. A 50% improvement would still vastly improve the quality of my life. There are many side effects I would accept to have such an improvement. Yet as David Tuller and Geraghty have written so brilliantly, the PACE trial did not offer any such thing. The results were truly pitiful. They were as far away from a cure as it is possible to get.
Lastly, I am going to address how it is written above that 'Keeping in mind that CFS/ME is diagnosed based on subjectively reported symptoms, it is not strikingly odd that trials focus on patient reported outcomes.'
This demonstrates gaps in the authors' knowledge of M.E. Yes, some symptoms are subjectively reported by sufferers. There are others which are easily objectively measured. Post-exertional malaise is one of them (see, for example, here https://www.researchgate.net/publication/243969294_Discriminative_Validity_of_Metabolic_and_Workload_Measurements_for_Identifying_People_With_Chronic_Fatigue_Syndrome). Julia Newton has done some excellent work on orthostatic intolerance. The PACE team themselves were set to measure how many steps trial participants took before and after the trial. This was abandoned. That would have been a really fantastic way of proving that CBT or GET worked. Why was this objective data abandoned? Because CBT and GET are ineffective and largely make no difference or make M.E sufferers worse.
Really none of the above is hard to grasp if you truly care about how patients experience this terrible illness.
A Moss
"It is difficult to understand why the benefit of CBT and exercise in patients with cancer and multiple sclerosis seems widely accepted, whereas the usefulness of CBT and GET for patients with CFS/ME remains controversial".
PACE version CBT and GET for ME/CFS is not the same as what is offered to people with Cancer and Multiple Sclerosis. PACE version is not your standard therapy for people trying to cope with their illness. People with Multiple Sclerosis and Cancer don't have to deal with the PACE proviso or have it foisted on them that their beliefs and lack of exercise are what is causing their disease. PACE CBT and GET also does not help most people with ME/CFS as the PACE authors papers show – yet it has been blanketed out like a prescription 'cure all' with irresponsible media and also given far too much weighting in health guidelines around the world.
This approach has been sold so strongly that when patients don't respond (which is a very large majority), people with ME/CFS blame themselves, health professionals blame them – as well as families. They either get labelled as being non-compliant, not trying hard enough or as difficult. If they refuse that reinforces the stigmatising prevailing views of patients. People with ME/CFS are abandoned by families, parents of children with ME/CFS get referred to child protection services at a far higher rate than should be happening as talked about on BBC file4. How is this helping patients? If anything this only puts those it does not help into vulnerable situations.
The physical impairments, cognitive impairments and functional difficulties are completely ignored, so people can't get supports and ME/CFS isn't classified as a disabling illness in many countries.
This is a public health mess and it is inhumane. Guidelines around the world have applied the PACE CBT/GET prescription regardless of how many it actually helps and the cruel judgements it empowers.
In the way that PACE has approached CBT and GET, it has done more to alienate and stigmatise than to help, the ironic and sad part is that if standard unforced versions were offered in order to help 'cope' with an illness/disease there wouldn't be such uproar and a lot more people would likely be helped.
The CDC has just recently removed their blanket recommendation for CBT and GET. It is time to stop blaming patients and conflating what the real problems are please, this is sad and it hurts people. It's about health care and helping people whether it has the 'bio' or "psychosocial" components or not.
Dr Brurberg writes that
This is not difficult to understand. CBT and GET for CFS are being promoted as a cure in the belief that the illness is being perpuated by thoughts and behaviour. There's no credible evidence for this illness model being correct or for CBT and GET having more than nonspecific effects.
This comment demonstrates a complete lack of understanding of the difference between the supportive CBT in cancer and MS that aims to help patients cope with symptoms, and the directive CBT in ME/CFS that aims to change illness beliefs, and in consequence change the way patients respond to subjective questionnaires.
The GET comment fails to acknowledge the biomedical evidence that energy metabolism and hence ability to exercise safely is altered in ME/CFS, as demonstrated in 2 day CPET tests and metabolomic studies. This means that GET is harmful in ME/CFS patients, whereas it can be potentially helpful in many other conditions.
If Keith Geraghty's article and subsequent articles that point out the fatal flaws of the PACE trial discourages other researchers from carrying out equally unscientific work, that is to be welcomed.
Carly Maryhew
"A large number of trials have consistently shown that cognitive behaviour therapy (CBT) and graded exercise therapy (GET) may be supportive for patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)."
Only in PACE and other methodologically unsound studies from a small group of researchers, nearly all of which rely upon using a diagnostic criteria which has little in common with ME/CFS. The Institute of Medicine in the US has specifically rejected such studies in forming an ME/CFS evidence base, and even NICE diagnostic criteria require much more than simple chronic fatigue.
The CBT used in ME/CFS is drastically different than the supportive CBT used in other biomedical illnesses. CBT-for-ME/CFS is explicitly based on ignoring symptoms and denial of illness, not on accepting illness and adapting to it. Frankly, it's shocking that self-purported expert on the topic would not know this. And it should be obvious that giving a vastly different therapy the same name as another therapy does not make the two therapies equal. Additionally, GET is not the same as "exercise", and cancer and MS are rather distinct from ME/CFS, in that ME/CFS is specifically defined by exercise intolerance.
"We are researchers and clinicians who think that health personnel should meet all patients, including those with CFS/ME, with respect and empathy, and offer the best available treatment with documented effects."
Laudable – but if that really is the goal, why are actometers and other objective measurements now routinely omitted? We don't want to just be brainwashed into saying we feel a bit less fatigued. We want to be able to be more active, to go back to work, to walk up a flight of stairs without suffering for hours afterward, to take a shower more than once a week, and even to be able to sit up in bed for the most severe. But the research, including PACE, shows evidence that CBT and GET don't make any of that happen.
"They have undertaken to make detailed protocols and statistical analysis plans available for the public – an example for other researchers to follow. Transparency highlights any differences between the protocol and the final product, but this does not mean that all changes to the original plan are inappropriate."
And then the PACE authors ignored their own protocol, to define "recovery" thresholds to be lower than the recruitment thresholds for a group of very ill patients. Then they wrote articles complaining about patients using ridiculously strict criteria to re-evaluate the data – even though that criteria was not strict, and was exactly as defined in the PACE trial protocol. Someone would have to be in complete denial of reality to believe that a score of 60 (range 0-100) on the SF36-PF subscale is anywhere near normal or healthy.
"Keeping in mind that CFS/ME is diagnosed based on subjectively reported symptoms, it is not strikingly odd that trials focus on patient reported outcomes. There is also a paucity of reliable objective outcomes for this condition."
Again, the ignorance displayed in this comment is shocking. The two-day cardiopulmonary exercise test (CPET) shows a distinctive worsening on a maximal CPET undertaken 24 hours after a prior maximal CPET. There have been at least half a dozen studies of this so far, with more underway, by at least 3 independent teams of researchers around the world. The tilt table test also usually indicates orthostatic intolerance in ME/CFS patients, numerous immune markers are consistently abnormal, etc. Actometers were originally promised as an outcome measurement, and even purchased, then their use was withdrawn from PACE.
"Even though PACE demonstrates that maximum heart rate or lactate levels remains constant or improves slightly following GET, it is appropriate to ask what it means for the patient."
Lactate was never measured, and heart rate, if it was measured, was not a reported outcome. Hence your statements here seem to be false, or based on insider information which is being withheld from the public. Step test results were never published, except as a graph with no numerical values. Software extrapolation from that graph indicated no improvement or a small decline in GET patients, compared to the pseudo-control group.
"One would therefore expect some degree of correlation between reliable and valid patient reported outcomes and objectively assessed activity levels, as substantiated by recent validation studies (Mahieu et al, 2016)."
One might expect many things, but in this case we can let reality guide us. In a review of three Dutch CBT/GET studies (Wiborg 2010), it was shown that all of the actometer data contradicted the glowing reports of less fatigue. This is not surprising, since CBT is geared at promising patients that they'll get better if they stop thinking they have fatigue. After such an education over several months, it's to be expected that some patients, when questionned, will want to be good pupils and tell the teacher that they are less fatigued.
"Retaining this perspective, PACE shows that some patients will improve very much following CBT or GET, and the majority will experience some improvement."
Again, this is simply not true. It's understandable that a journal was unwilling to publish outright falsehoods, and it's disturbing that Mental Elf is willing to do so. Perhaps you are under the impression that someone's claim of a 60% recovery rate in a pro-PACE letter was accurate, but that was later corrected or retracted. And reaching a score of 60 on the SF36-PF can indicate a decline for a patient who was admitted to the trial with a score of 65, in addition to that score indicating a substantial degree of disability.
"The effectiveness of CBT and GET was consistent no matter what case criteria that were used (White et al, 2011)."
That's only true if the effectiveness was shown in the first placec – it was not. Additionally, Oxford criteria require that fatigue be the primary symptom, whereas other criteria focus on exercise intolerance as a core symptom. Since many patients would not list "fatigue" high on their list of complaints, compared to chronic pain, headaches, orthostatic intolerance, exercise intolerance, ataxia, tachycardia, etc, using Oxford as the primary recruitment criteria would effectively exclude a great many ME/CFS patients. Additionally, the London ME criteria aren't recognized or used by pretty much anyone, probably due to being so vague and fatigue focused.
"These results are consistent across several outcomes within PACE, and across several other independent trials as confirmed by systematic reviews."
This does not defend or support the outcomes of the PACE trial, especially since those other trials suffered from even worse methodology – eg, there was often no attempt to screen for any physical disability at the start of those trials. And many were uncontrolled or poorly controlled, which means that any natural improvements in the course of the illness, especially from learning to avoid over-exertion, would be unaccounted for. And all trials with long-term followup, including PACE itself, show no benefit from CBT or GET.
"Clinicians should talk with patients about available treatment options, and patients can then decide whether they want to try CBT, GET or other approaches."
Patients need to make an informed decision. And that means knowing that there have never been indications of objective improvement, and even subjective improvements are meager at best. They also need to know that a large majority of the thousands of patients surveyed by several charities report that GET harmed them.
"Peer-review and debate are important constituents of science, but we are concerned that tendentious criticism and allegations as set forth by Dr. Geraghty (2016) are counterproductive and may discourage further research."
This is utter nonsense, and suggests that the entire scientific process should be shut down so that patients can continue to believe that unproven treatments will help them. Rigorous debate is absolutely critical to science, and researchers should welcome it when flaws and weaknesses are pointed out. That is how we improve. You simply do not get to label someone with a contrary viewpoint as being too harmful to be allowed to speak.
"An effect seen at an aggregated level does not imply that all patients will experience a benefit"
And yet PACE is used to deny patients any further assistance with symptoms, user to deny patients further testing to confirm if symptoms are purely CFS/ME and also to deny them benefits and support on the basis that purely psychological interventions should have made them better.
I *am* one of those patients. Want to swap lives with me? I'm in my 30's and cannot get any help at all because your friends have taken over the medical establishment here and have made CFS and ME effective DNRs on medical records!
And rigorous means being able to enter the study at 65% adult function band leave it at 60% and be considered recovered? At a level that is less than a congestive heart failure patient?
Open your eyes. Stop looking at the paycheck and look at the millions of people you are hurting who need the treatment of CFS and ME to change!
"All trials should be appraised according to the same criteria, and all possible shortcomings should be assessed with regard to the likelihood that they lead us to draw erroneous conclusions. In the case of PACE, we consider the conclusions to remain stable."
I find this completely unbelievable.
The PACE trial in its original protocol chose an SF-36 physical functioning questionnaire score of 65 as disabled enough to enter the trial, and 85 as evidence of recovery, (fully healthy adults of that age group would be expected to score 100).
When they published the recovery paper, they switched the recovery score to 60. In other words they claimed patients who were sick enough to enter the trial had somehow magically recovered by getting worse. Using this new ridiculous criterion (combined with their other weakened subjective recovery criteria) they claimed 20% of patients in the CBT and GET groups 'recovered'.
They refused to publish the percentages based on their original protocol recovery criteria and wasted over £200,000 public money fighting an FOI request for the data so this analysis could be done. They lost.
When the data was re-analysed according to the protocol, all groups had recovery percentages in single figures and there was no between group difference.
Decent scientists aiming to find the truth would acknowledge they had got it wrong, and retract their recovery paper. That was not done, and the PACE authors continue to claim PACE shows GET and CBT are effective.
This is not an example of good honest science.
NxOwl
" It is difficult to understand why the benefit of CBT and exercise in patients with cancer and multiple sclerosis seems widely accepted, whereas the usefulness of CBT and GET for patients with CFS/ME remains controversial."
Really, so you're writing an article on ME/CFS without knowing about its main symptom: Post-exertional malaise/Post-exertional neuroimmune exhaustion?
Well, sir, that sets it for me at least and I think it would for any person with some working neurons that could process basic logic.
"No bias, no misinformation, just this elf talking without basic knowledge of the subject he is onto."
Three objective measures were planned for the PACE trial.
The 6 minute walk test, for which so much data at 12 month follow up is missing as to make the results unreliable,
The step test, which has not been published except in a tiny graph which suggests no between group differences, and for which data release for further analysis has been refused,
And the wearing of actometers which was done at the start but never published, and abandoned as a 12 month follow up measure.
One can only conclude from this that the PACE authors did not want to risk showing that questionnaire based improvements were not matched by any measurable improvement in physical functioning. Is this the action of good scientists who want to learn the truth?
Please could you point to where this is published. I have not seen any mention that I can recall of lactate or recording of heart rate in any of the PACE papers.
"PROMs are often more important to patients than objectively assessed outcomes, and researchers should therefore avoid devaluing PROMs on a general basis. "
This completely misses the point that using subjective measures in an unblinded trial holds such high risk of placebo and therapist effect that it is never used in unblinded trials in other areas of medicine. Subjective outcomes are only scientifically valid measures of real difference in outcome if the patient does not know whether they have had an active treatment or a placebo, so their response cannot be influenced by wishful thinking or loyalty to a therapist.
Given that the between group differences at long term follow up had disappeared, and the reanalysis of recovery data using the original trial protocol showed no statistically significant difference between groups, it can only be reasonably concluded that GET and CBT are ineffective for ME/CFS.
Given also the biomedical and patient survey evidence demonstrate that GET is harmful for people with ME/CFS, and that the PACE and FINE trials show no significant benefits, all recommendations of these treatments should be withdrawn, as has been done by government health bodies in the USA.
James C. Coyne
This is an utterly dishonest account. Brurberg was offered an unusual opportunity to nominate reviewers for a reconsideration of his manuscript. He was explicitly told to ensure that nominations were free of conflict of interest. What did he do? He reached deep into the PACE investigator old boy network.
Brurberg needs to take an ethics class.
See my full account here
https://www.coyneoftherealm.com/blogs/news/misconduct-in-an-author-s-nomination-of-reviewers-for-his-manuscript
To be fair to Dr Brurburg, it must have been a near impossible task to find a reviewer without a conflict of interest who would not have torn his commentary to shreds. I'm not aware of any disinterested academics who are willing to defend PACE.
jimells replied:
Thank you Robert McMullen. Your comment really made my day.
The claim that I have nominated reviewers with known conflicts of interest is simply not true. When asked to nominate reviewers to my own work, I find it important to suggest people who holds the needed distance to me and my work. As the distance increases, it becomes increasingly impossible to have a full overview of peoples' social life during the last decade. I did not know that one of the suggested reviewers had been sitting next to one of the PACE-authors at a conference dinner, but I would not consider this as a serious conflict of interest.
It should not be regarded as dishonest for authors or reviewers to have an opinion on disputed matters as the PACE trial.
You state in your blog: "It is important to consider, in addition, your own conflicts of interest as a person who worked for the Cochrane Collaboration in the analysis of individual data on exercise therapy for CFS including data from the PACE Trial…."
Despite being aware of my "conflicts of interest", Journal of Health Psychology invited me to write a commentary on Geraghty's editorial on the PACE trial. You did not declare however that JHP has intellectual conflicts of interests regarding the PACE trial, by only accepting reviewers representing the critics of the PACE trial, and rejecting papers from authors not sharing your views on the PACE trial.
If I had known, I would not have accepted the invitation.
Carly Maryhew replied:
Having an opinion about a topic, and even an actual conflict of interest, does not disqualify someone from contributing to a conversation on that subject. I have every confidence that your commentary would have been published if it met the relevant requirements for publication.
But to review your commentary to assess its success in meeting those requirements, unconflicted reviewers were requested. Perhaps your recommended reviewers were not your good buddies, but they were obviously highly conflicted on the subject of PACE. Surely you can see how that is inappropriate for a commentary regarding PACE?
There are also numerous problems with your commentary as published here by Mental Elf, which are detailed by myself and many others in the comments below. Some of the issues with your commentary involve outright falsehoods (hopefully inadvertant), which make your statements unsuitable for publishing anywhere. Hopefully you will respond to those points in detail. But given the lack of substance in your commentary thus far, I expect more of the evasion we have consistently seen from PACE supporters thus far.
Grumpy Ninja replied:
I note for the record that Dr Brurberg's two responses (so far) to comments have not even attempted to address a single technical criticism or question.
Art Vandelay replied:
The PACE authors and their supporters have shown no interest in addressing criticism of their work. Rather, they prefer to respond either with obfuscation or with (unfounded) claims of harassment,
They seem completely unable to cope when they are removed from the small pond of psychiatry and are faced with serious scientific debate.
Robert McMullen
There are so many errors in this commentary it is hard to know whether the authors are being disingenuous, or whether they have failed to understanding the relatively straightforward arguments put forward by Dr Geraghty and others in the JHP.
I note there are no conflicts of interests declared by Kjetil Gundro Brurberg, Signe Flottorp and Aase Aamland. Given the apparent bias of the commentary, I would be surprised if none exist.
They write: "It is difficult to understand why the benefit of CBT and exercise in patients with cancer and multiple sclerosis seems widely accepted, whereas the usefulness of CBT and GET for patients with CFS/ME remains controversial."
It is hard to believe that such an assertion could be made by anyone with any familiarity of the issues surrounding PACE. As others have pointed out, the type of CBT given to PACE participants is not the same as the CBT given to patients with cancer and MS. ME/CFS patients in PACE were told that their symptoms were perpetuated by false beliefs; that they could be cured by their own efforts by thinking differently and pushing themselves to do more and more. CBT given to cancer and MS patients is very different. It acknowledges patients' physical symptoms and helps them to manage their activities within the physical limitations of their disability.
As for exercise, post-exertional malaise (PEM) is a required symptom for a diagnosis of ME/CFS to be considered. It is not a required symptom for MS or cancer. If patients get better through exertion (as prescribed in PACE) they do not have PEM, and therefore they do not have ME/CFS.
Instead of dissecting all of the errors in the commentary above, I would urge anyone who is not familiar with the controversies surrounding the PACE trial to read all of the commentaries in JHP which can be accessed here: http://journals.sagepub.com/action/doSearch?content=articlesChapters&countTerms=true&field1=AllField&publication=hpqa&target=default&text1=%22pace+trial%22&startPage=0&sortBy=Ppub
I would also recommend reading the following open letter to Psychological Medicine:
http://www.virology.ws/2017/03/23/an-open-letter-to-psychological-medicine-again/
It is also notable that the CDC has recently removed CBT and GET as recommended treatments for ME/CFS:
http://www.meassociation.org.uk/2017/07/cdc-removes-cbt-and-get-as-recommended-treatments-for-mecfs-11-july-2017/
Finally, if you have not already done so, please consider signing the MEA petition calling on NICE to revise its ME/CFS guideline (ends 21 July): https://www.change.org/p/petition-the-nice-guideline-for-cfs-me-is-unfit-for-purpose-and-needs-a-complete-revision
This is the second time that a site that is supposed to expose bad science publishes a defense of what has been widely criticised as bad science – and one written by someone who is hugely biased at that. I am puzzled as to why.
I am heartened by the well-reasoned and well-researched critique in the comments but we shouldn't even have to have this conversation. The PACE trial has been widely criticised by people who understand the subject, and the demands for its retraction should be welcomed. People with ME/CFS deserve so much better than being told that if they just stop thinking they have an illness, they will stop being ill. If we did this to people with literally any other long term condition without any attempt to address the underlying pathology, there'd be a public outcry.
Readers of Dr Brurberg's article may also be interested in James Coyne's blogpost -https://www.coyneoftherealm.com/blogs/news/misconduct-in-an-author-s-nomination-of-reviewers-for-his-manuscript – which details how Dr Brurberg's commentary was rejected by the JHP after he knowingly nominated 'independent and unbiased' reviewers for his article who in fact had close associations with the PACE team and obvious conflicts of interest.
I'm not sure who comes out of this worse – Dr Brurberg for the way he's conducted himself, or Mental Elf for publishing his account without apparently bothering to make even cursory enquiries with the JHP as to what actually happened.
"No bias. No misinformation. No Spin." reads the slogan at the top of this page. After publishing Dr Brurberg's blogpost that looks like a pretty empty and inaccurate claim.
Art Vandelay
Scepticism and calls for transparency are an integral part of science. Open debate will most likely only scare away the pseudoscientists, charlatans and snake-oil salesmen from conducting their dubious research. (Indeed, one can only hope.) After all, they are the ones who have the most to hide.
I doubt proper scientists like Prof. Ron Davis would let scientific criticism of his work dictate whether he continues with his study into ME/CFS.
Ian Stirling
Quoting the NICE guidance at:
https://www.nice.org.uk/guidance/cg53/chapter/1-Guidance#general-management-strategies-after-diagnosis
6.2.10 CBT for a person with CFS/ME should be planned according to the usual principles of CBT, and should include: *(This is not normal CBT)
Explaining the CBT approach in CFS/ME, such as the relationship between thoughts, feelings, behaviours and symptoms, and the distinction between causal and perpetuating factors.
(The basis of this treatment is the illness is driven by a fear of normal exercise symptoms leading to rest, weakness, and more symptoms on exercise of weak muscles. There is no physiological explanation given of this that makes sense from an exercise physiology point of view as applied to symptoms of patients, not a caricature of them)
Discussing the person's attitudes and expectations.
Developing a shared formulation and understanding of factors that affect CFS/ME symptoms. (convincing the patient that their symptoms are normal)
Establishing a stable and maintainable activity level (baseline) followed by a gradual and mutually agreed increase in activity. (trying to do 'gradual increased baseline' of activity has left me mostly housebound for around a decade now).
Challenging thoughts and expectations that may affect symptom improvement and outcomes. (This is a direct restatement in more clear language 'if you ignore the symptoms, you will get better')
Addressing complex adjustment to diagnosis and acceptance of current functional limitations. (with the implication that most people get better – not several percent as in fact found in studies)
Developing awareness of thoughts, expectations or beliefs and defining fatigue-related cognitions and behaviour. (And then how would this affect the patients filling in of questionaires on their illness used to prove the treatment works)
Addressing any over-vigilance to symptoms and related checking or reassurance-seeking behaviours by providing physiological explanations of symptoms and using refocusing/distraction techniques. (The 'physiological explanations' given are essentially lies, when considered for more than several minutes, they are based around normal exercise outcomes, and are wrong in timescale, symptom spread, location. Muscle pain following exercise occurs only in the exercised muscle group in normal people, not all over the body)
I speak as a CFS patient of some 30 years, getting more impatient as we speak.
I currently have sore arms, because I was able for the first time in a couple of years do some hedgetrimming. And yet the week before, I was knocked out for several days following doing the vacuuming for the house properly.
I'm not avoiding activity, or scared of the normal consequences. I have an unpredictable ceiling on my activity that if I exceed it causes symptoms that are not normal exercise symptoms.
Treatments based on ignoring the symptoms I have, and parodying them as normal exercise symptoms are dangerous. It is as bad as characterising cancer as an exaggerated fear of lumps.
I note that many commenters have already made several eloquent points. I hope to not be too repetitive. I have not addressed all the issues with this commentary, only some key ones.
1. "A large number of trials have consistently shown that cognitive behaviour therapy (CBT) and graded exercise therapy (GET) may be supportive for patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)"
Actually, a large number of unblinded trials using subjective measures have claimed to be an effective treatment for ME/CFS, based on the deconditioning/activity avoidance model, which posits that the illness is a post-infectious syndrome perpetuated by deconditioning, which is itself perpetuated by activity avoidance and "false illness beliefs" that activity will exacerbate symptoms. The two treatments of Graded Exercise Therapy (GET) & Cognitive Behaviour Therapy (CBT) aim to treat this hypothesised underlying dysfunction and lead the individual back to health. To claim that they have been positioned as supportive therapies is misleading, to say the least. These therapies have been promoted as remedies, and many health professionals and government agencies view them that way. As a direct result, parents have been referred to family services, some have had children removed from their care because these treatments have been accepted as primary treatments (not adjunctive therapies), and parents who refuse these treatments for their children often face serious consequences. Others have been denied access to much needed supports because those service agencies have been led to believe that ME/CFS can be treated with exercise. Individuals with ME/CFS and their families have been denied support services and rejected by health professionals when they either do not respond to their treatments, claim to be worsened by them or refuse to undertake them. The damage caused from this research base claiming to be a remedy for this condition is significant.
2. "This observation tells us nothing about the possible or plausible causes of the disease."
The PACE authors hypothesise a very clear cause of the condition, in the combination of deconditioning and activity avoidance. This hypothesis is testable. When the evidence does not support it (which it doesn't, see below), it should be rejected.
First of all, it is important to note the distinction between CBT as it is used with chronic illness, and CBT as it is used within the deconditioning/activity avoidance model of ME/CFS. With other chronic illnesses, such as MS, CBT is an adjunctive treatment which does not aim to treat the underlying pathology (ie: demyelination), but is used as an aid to coping with, and adjustment to, living with such a condition. By comparison, in the deconditioning model of ME/CFS, one of the core pathologies is hypothesised to be "false illness beliefs" which lead the individual to avoid activity. The CBT treatment therefore aims to address these false illness beliefs, which are thought to be obstacles to activity, such that the individual can be reconditioned and then recover. These two forms of CBT have different aims, and are therefore very different.
No doubt if people with MS or cancer were being given CBT on the assumption that their primary pathology was maladaptive cognitions, and if what meagre research funding there was was going into further studies into this notion of their dysfunctional cognitions, I doubt that they would be accepting of these treatments either. CBT as an adjunctive treatment for ME/CFS, where it is used to help people cope with their illness, can be very helpful. However, that it not how CBT is applied within the deconditioning model, or within the PACE trial. The PACE authors and Brurberg are disingenuous in not making this distinction between these two very different approaches to the use of CBT.
A further reason why there is objection to these treatments is that a core feature of this condition (as confirmed by the National Academy of Medicine's (NAM) 2015 report) is exertion intolerance, which means that symptoms are exacerbated by activity. This is not a feature of conditions like MS or cancer. Exertion intolerance has been reliably and repeatedly measured in tests like the 2-day cardiopulmonary exercise test (CPET), an objective measure which can distinguish between lack of physical capacity and lack of effort (ie: it is not easily faked). For this reason, and based on the NAM report, the CDC recently removed the recommendation for GET and CBT from its treatment recommendations. When exertion intolerance is a cardinal feature of the condition, it is understandable that patients have concerns about such treatments. To understand exertion intolerance and Post-Exertional Malaise (PEM) and to recommend exercise to such patients is akin to recommending sugar to diabetics. At what point does this become negligence?
3. "Where he [Geraghty] sees dishonesty and fraud, we see a transparent, well-conducted and rigorous trial."
You may well see a transparent, well-conducted and rigorous trial, however, outside of the PACE authors' colleagues, you would very much be in the minority.
In 2016, more than 40 ME/CFS researchers signed an open letter to The Lancet calling for the original PACE study to be independently reanalysed, due to significant concerns they had:
http://www.virology.ws/2016/02/10/open-letter-lancet-again/
In 2017, more than 100 ME/CFS researchers and organisations from around the world signed an open letter to Psychological Medicine seeking a retraction of the follow up paper on recovery, due to its significant flaws.
When those outside of the ME/CFS field read the PACE trial, they more often than not join the loud voices articulating its flaws. Just one example is Professor Rebecca Goldin's (professor of mathematics, and Director of STATS) critique:
http://www.senseaboutscienceusa.org/pace-research-sparked-patient-rebellion-challenged-medicine/
Very few independent analyses agree with your assessment of this trial.
4. "There is also a paucity of reliable objective outcomes for this condition"
"PROMs are often more important to patients than objectively assessed outcomes, and researchers should therefore avoid devaluing PROMs on a general basis."
As other commenters have said, the issue here is when subjective measures are used with non-blinded trials. Such trials are highly likely to be subject to bias, of which the author, as a Cochrane reviewer, would be well aware.
There is another issue with the use of subjective outcome measures with CBT. The aim of CBT is to alter the individual's thoughts and, consequently, their behaviours. Subjective measures simply provide an indication of whether the treatment was successful at changing beliefs. That self-reported ratings change as a result of a treatment designed to change self-report ratings says nothing about the state of the underlying condition. To test both the usefulness of the treatment to treat ME/CFS and the underlying deconditioning/activity avoidance hypothesis, objective measures are needed and have been called for.
There are several objective measures that have been used unfortunately not often enough. The PACE trial incorporated a 6 minute walk test, and a step test. They also began to use actimeters, but these were dropped. When objective measures are utilised in GET studies, the results are less than impressive. On average, after 52 weeks of treatment in the PACE trial, participants performed about as well as someone with congestive heart failure, and far worse than a healthy adult. Whilst subjective measures give an indication that the individual's beliefs may have changed (or that they are attempting to meet experimenters' expectations), objective measures suggest that the hypothesised deconditioning has not been reversed following this course of treatment. Research to date does not support the deconditioning hypothesis of ME/CFS and it should be rejected.
5. "Peer-review and debate are important constituents of science, but we are concerned that tendentious criticism and allegations as set forth by Dr. Geraghty (2016) are counterproductive and may discourage further research. Patients who could benefit from these treatment strategies, and actually want to try, may also lose the opportunity because they lose the courage to try or because health personnel avoid offering them."
Undermining a critical voice, by implying that his critique would be responsible for either discouraging researchers from the field or patients from trying the treatment is gaslighting. Science requires robust critique. If the PACE trial is unable to withstand such critical analysis, then this suggests that it is highly flawed (an opinion to which many adhere). Contrary to the author's assertion that patients may miss out on this treatment as a result of Dr Geraghty's critique, the issue is quite the opposite. Currently, in many places in the world, GET and CBT are the ONLY treatments offered to patients. Patients who reject them, don't respond to them or become worse as a result of them are viewed as difficult, considered to be overly identified with the "sick role" and thought to not want to recover. In other words, their lack of recovery or adverse reaction to the treatments is blamed on the patient, rather than on a flawed model and inappropriate treatments.
Given the flaws in the PACE trial in particular, but also other GET/CBT trials (broad diagnostic criteria, subjective outcome measures), the repeated reports of harm from patients following GET treatment, coupled with the recent study highlighting that, even using subjective measures, 85% of patients at UK CFS/ME specialist clinics rate themselves as still having CFS/ME 2-5 years after treatment (see Collin & Crawley, 2017) (ie: the majority are not recovered, despite having treatment for the deconditioning which has been hypothesised as their core dysfunction), there is an obvious question: what if the deconditioning hypothesis is wrong? What does that mean for these researchers who have recommended that patients with ME/CFS engage in exercise to aid their recovery, and who have advised against rest? On an important level, this is an ethical issue. Patient care must be paramount. When there is a risk of harm to patients, all action must be taken to minimise or avoid that risk. Given the core nature of objectively measureable exertion intolerance to ME/CFS, recommending exercise as a treatment, based solely on highly flawed research base, and in the face of biomedical evidence supporting the likelihood of harm, is unethical. That the PACE researchers are unwilling to even consider the possibility that they may be wrong, that their recommendations may be causing harm both directly (through the treatments themselves) and indirectly (through how patients are treated by agencies and health professionals who believe the authors' spin on their results, and blame patients for their lack of recovery) is unethical.
The tide is turning. The psychosocial model (for it cannot be truly considered a biopsychosocial model, as it excludes all biological evidence) has been dominant for decades. However, biomedical ME/CFS researchers are increasingly finding their ducks lining up, highlighting exertion intolerance, impaired glycolysis, immune dysfunction, amongst other abnormalities. Yet pro-GET/CBT researchers are ostrich-like in their refusal to integrate any of the biomedical evidence into their model. But science requires it. Their hypothesis must incorporate new evidence. They hypothesise that the condition is caused by deconditioning and activity avoidance. For example, should the Rituximab Phase III trial be successful, how will they account for it within their framework? How would a b-cell depleter remedy deconditioning and false illness beliefs? Whilst the author might feel that Dr Geraghty's critique was unnecessarily harsh, the PACE authors and other proponents of the psychosocial model have greater foes to face as the biomedical evidence progresses and continues to mount. These new findings must be addressed within the model and, if it is unable to account for the evidence, the model should be rejected.
Peter Trewhitt
The authors state:
As other commenters mention, this comparison is at best disingenuous. PACE was explicitly based on the unevaluated hypothesis that ME/CFS, though possibly having an initial organic illness trigger, is a set of 'false beliefs' that exercise will make the condition worse, which in turn is reinforced and/or perpetuated by 'deconditioning'. In stating "This observation tells us nothing about the possible or plausible causes of the disease" the authors are either misinformed about the original PACE research or deliberately misrepresenting it.
In comparing research into use of CBT and GET with Cancer and MS patients, with the very specific PACE CBT aimed at curing patients of their 'false beliefs' about the nature of their condition, the authors are not comparing like with like. If that was the case the studies they cite would involve attempts at making Cancer patients and people with MS believe that their cancer did not exist or their MS was a 'false belief'.
There are now thousands of studies indicating an organic basis for ME/CFS, some cited by other commenters here, that go against 'the false belief and deconditioning model' that the PACE research is based on. Why have none of the PACE appologists attempted to evaluate this model? There has been no study demonstrating ME/CFS is the result of false beliefs and deconditioning.
As an ME/CFS patient I have had CBT aimed at helping me adjust to having a long term disability, aimed at helping me not have unrealistic expectations about what I am able to do on a 'good day'. I found this very helpful. Obviously this is a subjective anecdote and not a scientific fact, but it helps illustrate that people with ME/CFS that condemn the PACE based CBT do so because of its content not because of an irrational aversion to the method of delivery. The use of CBT in ME/CFS is only now controversial because of its misuse by PACE.
jimells
Thank you for publishing this essay. It is much easier to ridicule the naked emperor when he is strutting down the street for all the world to see. As a mostly housebound patient, ridicule is about all I got left.
I feel the same way about the PACE trial. Patients were mistreated with therapy-and-exercise long before PACE was published. Yes it has been used to reinforce the abuse of patients, and that abuse continues unabated to this day, but its many obvious and irrefutable problems make it an easy target.
But now researchers and patient advocates are using PACE like Thor's Hammer to smash the entire therapy-and-exercise regime into dust. Even the CDC has finally changed its website to remove its promotion of therapy-and-exercise as "the cure".
The more that PACE supporters whine about criticism from researchers and patient advocates, the sillier they look. So please keep telling us how fine your new suit is. I can always use a good laugh.
"Our contribution was intended to bring perspectives into the debate, aiming for better understanding and lower levels of conflict. Sadly, JHP decided to reject our contribution, essentially stating our arguments to be well known and erroneous. We consider it disturbing when a closed editorial process is used to label opinions as right or wrong. For such a strategy to work, the process needs to be transparent and unbiased. JHP does not seem to satisfy this standard, and authors who are supportive to the PACE trial and the PACE-trialists may seem selectively rejected.
This account of the rejection of their commentary differs marked to that of the JHP, see
https://jcoynester.wordpress.com/2017/07/19/misconduct-in-an-authors-nomination-of-reviewers-for-his-manuscript/
I have no privileged access to the current authors' motivation or the JHP's editorial decision so suggest readers look at both sides of the argument, bearing in mind The Mental Elf's aspirational strap line "NO BIAS. NO MISINFORMATION. NO SPIN."
However, along with the other commenters here I am strongly of the view that this article demonstrates all three: bias, misinformation and spin.
Grumpy Ninja
1. PACE was not properly controlled, and was denied that status by the reviewers. (One of the things they did get correct.)
2. The two alternative criteria used in PACE (CDC CFS, and London ME,) were i) not used as entrance criteria, and ii) were modified in ways that made their results incomparable with other trials using those criteria.
3. The Adaptive Pacing Therapy arm, that was supposed to be the version of informal activity self-management that patients prefer ('pacing'), bore only passing resemblance to pacing as practised by patients. APT has also only be used in PACE, and so its results also cannot be compared to other trials.
4. There is no body of objective or properly blinded subjective evidence for sustained, clinically significant benefit of CBT and/or GET for CFS or ME. Even PACE itself found no benefit at long term follow up, a rather critical finding, one would think, for a definitive trial.
5. The sum total of the achievements of PACE, and similar trials, is getting a small % of patients to make small and clinically insignificant changes in their self-report questionnaire-taking behaviour, with no correlation to or support from objective measures, and no sustained effect. This is not a useful therapy in any meaningful practical sense.
6. This null therapeutic result clearly also fails to provide any support for the psycho-behavioural causal model providing the rationale for using these forms of CBT and GET.
7. These CBT/GET trials are, in effect, typically little more than attempts to maximise known methodological confounders in psychological research, and then arbitrarily relabel the trivial combined generic effect as a specific significant therapeutic benefit.
Whether deliberate or not, I leave to history to judge. But I do note that history is rarely kind to those who produce, promulgate, and profit from such obvious and unethical nonsense.
It is reassuring to read such a detailed and informative article. As an M.E. sufferer I have become increasingly incredulous of the criticism of the PACE trial. The more I have read the original trial publications rather than relying on second hand accounts, the more apparent it has become that a distorted narrative has arisen that does not serve the best interests of people with M.E. It would be far more productive and fairer to all involved if those who want to advocate genuinely for people with M.E. could focus on the broader issues such as ensuring that where patients undertake CBT/GET that it is safely applied as it was in PACE and therefore does not result in harm, on promoting better treatment from the broader medical profession for people with M.E. and on correcting common misconceptions among patients about what the PACE trial does or doesn't say.
Please could you be more specific? Which of the criticisms of PACE published in JHP do you disagree with, and why?
Anton Mayer (@MECFSquestions) replied:
Some PACE apologist feels they need to impersonate a patient supportive of CBT/GET in order to defend the trial. That says a lot about how defensible it really is.
DW, it is important, especially given the perception of so many people with ME that the PACE advocates have in the past actively briefed against the patient community, that all contributions are welcomed to this debate.
Your views are important, but if we are to understand them we need specific examples where the 31 comments currently visible above, all of which disagree with specific issues raised by the authors, are the result of "a distorted narrative" "relying on second hand accounts" rather than a genuine attempts to respond to factual inaccuracies and misleading spin on the part of the current authors.
Anne replied:
As an ME patient, are you satisfied with a trial that defines recovery as a score of 60 on the SF36 scale, when healthy people range from 90 to 100?
A score of 60 is close to the mean physical function score of patients with Class II coronary heart failure. 1
If you are, I'm not, and I don't think there are many patients who are pleased with this definition.
1. Juenger, J; Schellberg, D; Kraemer, S; et al. (Mar 2002), "Health related quality of life in patients with congestive heart failure: comparison with other chronic diseases and relation to functional variables", Heart, 87 (3): 235–241, PMID 1767036
It's a funny thing about the PACE trial – it disproves itself. It's right there in the abstract for the paper titled "Rehabilitative treatments for chronic fatigue syndrome: long-term follow-up from the PACE trial":
"There was little evidence of differences in outcomes between the randomised treatment groups at long-term follow-up."
It's right there in black-and-white: exercise and therapy don't work. End of.
You only need to look at the fitness and six minute walking tests to see the treatments are placebos.
adrian replied:
PACE doesn't say how to 'safely' apply CBT or GET because they failed to measure compliance and activity increases. So we don't know if the trial participants increased activity or just reported that. No figures are published and no measurements taken. We do however, have reports of harms from patients who attend the CFS clinics – but those clinics appear to have no system for reporting harm.
One of the reasons for analyzing the PACE trial is to try to increase the standards of research. The whole idea of having an open label trial measured with subjective outcomes where the interventions aim to change illness views is so wrong. The shocking thing with PACE is given this poor methodology that they did not get better results.
It is of course not just patients who are complaining about the methodology but academics who have been shocked by the methodological failures.
Whilst PACE stands it allows bad research to happen and over promotes ineffective and potentially dangerous treatments.
"The shocking thing with PACE is given this poor methodology that they did not get better results. "
You got that right, Adrian. They didn't just put their thumb on the scale, they used an elephant. And even that barely moved the needle.
The PACE investigators have truly set a new standard when it comes to incompetence. I'll bet they were pleased to learn their work is already being used to teach young researchers how NOT to do research. After all, infamy is better than obscurity, right?
Sean Wilson
Dr Brurberg,
Your paper was rejected after the peer review process.
You nominated 3 referees, one of whom refused to review it and 2 others who were two close to ensure proper impartiality.
Can't you just accept the decision of the editor of JHP with good grace and submit a better quality paper the next time?
Dear Dr Brurberg,
I see you have responded to one of the comments here. I hope this means you are reading all the other comments carefully.
I do hope, as a scientist seeking to promote better quality research you will read all the comments as well as all the articles published in JHP critical of PACE and use your good scientific brain to examine objectively all the points raised.
It would be useful for you also to gain a better understanding of ME/CFS if you would read widely in the biomedical literature rather than just the the psychological literature.
This would be a good place to start, especially the summary of the biomedical evidence on page 3, but I think taking the time to read the whole document would be enlightening.
http://iacfsme.org/portals/0/pdf/Primer_Post_2014_conference.pdf
It is clear from your article that you do not understand the differences in the CBT done in PACE and in cancer care.
You also do not appear to be aware of the biomedical evidence showing problems with energy metabolism that make GET harmful in ME that make some of your statements inaccurate.
I do hope you will concentrate on the substance of the comments made here, rather than simply seeing them as criticisms and becoming defensive.
The fact that your article was rejected by JHP should, to a good scientist, flag up warnings that your article contains serious inaccuracies, rather than assuming that it is because your article is critical of Keith Geraghty's article.
A good scientist should have the humility to learn and to admit when they have got it wrong. I am sure you aspire to be a good scientist. I fear you have been taken in by the PACE and other psychological researchers who have their own agenda.
I address the same comments to the editors of Mental Elf who chose to publish this article.
Carolyn Wilshire
Dr. Brurberg, it is brave of you to publish your rejected article. It is never fun to receive a journal rejection, but few of us have the guts to reproduce our failed articles in this way. I cannot say whether rejection was justified or not. But many of the points you make are recognisable as part of the PACE authors' standard line of defense, and I encourage you to dig deeper next time.
I wish to comment on one particular point you make.
You say, "All trials should be appraised according to the same criteria…" However, your article is effectively advocating for the opposite state of affairs, where behavioural interventions are allowed to be judged as "high quality" even though they are not fully blinded and are therefore highly susceptible to patient self-report biases. Your wish seems to be that these trials should continue to have an unfair advantage over pharmacological trials, and that any bias due to non-blinding should simply be ignored.
Would you accept at face value a pharmacological trial that did not double blind? Of course not. But you are unconcerned by this issue when its effect is to unfairly favour the behavioural interventions you advocate.
You may say "Well, nothing to be done – these are behavioural interventions!". But that is no reason to ignore the possible biases a lack of blinding may introduce. Also, much CAN can be done. There is now a considerable body of literature available on how patient expectation affects different outcome measures, and about how biases due to nonblinding can be minimised and/or their likely effects estimated. If you genuinely wish for equivalency, then it is time to read that material.
You also do not seem aware of the fact that the PACE trial collected a number of objective outcomes, but the results for these outcomes failed to mirror those obtained using self-report measures. This is a hug red flag, because recent research shows that objective outcomes are less vulnerable than self-reported ones to expectancy effects. Therefore, being able to shows consistency of outcomes across both self-report and objectives measures is crucial in an nonblinded trial.
Finally, on the issue of recovery, I again encourage you to dig deeper. Do read our paper on the recovery definition used in the PACE trial (Wilshire et al., 2016), the PACE authors' defence, and our response to their defence. And then ask yourself again whether you still adhere to the party line on this matter, that it all just comes down to your particular view on recovery. Surely, you don't have to agree with the PACE authors on everything?
Keith Laws
To return briefly to the underpinning 'science' for a moment… Dr Brurberg says that "A large number of trials have consistently shown that cognitive behaviour therapy (CBT) and graded exercise therapy (GET) may be supportive for patients with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) (Larun et al, 2016; Price et al, 2008)."
As the most recent – and therefore, influential – meta-analysis, I wanted to make a few brief comments on the Cochrane meta-analysis of CBT by Price et al …and Dr Brurberg's reference to it
I was left asking myself… what is meant by the phrases: "large number" (of trials), 'consistently' and 'supportive'?
Assuming that some answers might be found in Price et al., it is worth taking a look. The key headline message in the Price et al abstract states that CBT significantly reduces fatigue scores at post-treatment. The analysis consisted of 6 trials and it is the largest number of trials assessing any outcome presented by Price et al…so, I guess 6 is a 'large number'
Are the findings consistent? Well, 2 trials found a significant CBT effect, but 4 were nonsignificant – are they consistent?….more consistently nonsignificant than significant?
In the broader context of the review, Price et al presented 44 separate (meta) analyses of various outcomes from 15 trials. Of those 44, only 9 analyses show better outcome for CBT than control (including 5 analyses that involved just a single study) – so, the majority of comparisons do not support CBT efficacy – In other words, approximately 1 in 5 of their analyses suggest CBT may be 'supportive'
At the finer level of individual effect sizes, Price et al present 128 effect sizes – of which 37 are significant for CBT, while 91 are non-significant – so fewer than 30% of individual CBT effect sizes are significant
So, wherever we look – the majority of analyses, outcomes and effect sizes reported by Price et al do not obviously or clearly (in my view) point to CBT being supportive in CFS
Another issue concerns bias….of the 15 studies examined by Price et al, only 1/15 can be deemed 'free of selective reporting', only 3 are blind and none of the 15 are deemed free from 'other bias'.
We might also note that the CBT for CFS trials assessed by Price et al are massively underpowered to detect the effects that they do propose as significant. For the main analysis on whether CBT reduces fatigue, the median power to detect true effects is remarkably low at .27 – although Price et al did not deem it necessary to remark upon poor study quality or the tiny sample sizes in their abstract or the Plain Language Summary (aimed at a wider audience) of their Cochrane review
Finally, Dr Brurberg raises the following interesting point
"It is worth noting that the effects of CBT and GET in CFS/ME are similar to those seen among patients with other serious diseases where fatigue is a prominent symptom, e.g. cancer (Furmaniak et al, 2016) and multiple sclerosis (Heine et al, 2015; van den Akker et al, 2016). The benefit of CBT and GET does not imply that we can conclude that cancer, multiple sclerosis or CFS/ME occur for psychological reasons. It is difficult to understand why the benefit of CBT and exercise in patients with cancer and multiple sclerosis seems widely accepted, whereas the usefulness of CBT and GET for patients with CFS/ME remains controversial."
It seems quite commonplace amongst CBT advocates to make such a argument – it centres on what I would call 'nominal analogy' assumption
if CBT impacts symptom X (fatigue) in disorder A (Cancer), then it will also impact symptom X (fatigue) in disorder B (CFS/ME). This argument is based on the assumption that identifying symptom X in both 'disorders' means they are identifying the same 'thing' … the symptom is abstracted and decontextualised …and hence it often follows, that the same treatment is applicable and possibly equally efficacious
It only takes a moments reflection to see that argument holds no (logical) water….….For example, CBT may reduce the symptoms of depression in those diagnosed with depression; however, other evidence shows that CBT does not reduce the symptoms of depression in Bipolar Depression (see Jauhar, McKenna & Laws 2016). If we turn back to the current case – Dr Brurberg cites the Cochrane review as evidence of CBT efficacy- even here it fails to show that CBT reduces depressive symptoms in CFS/ME… calling something a dog does not make it bark
Clark Ellis replied:
I hope you write more somewhere about this, your arguments are clear and logical and cut through a lot of the crap that gets spouted by others. Thanks.
Tom Kindlon
Robert Courtney & I wrote detailed critiques of the Cochrane review of exercise therapy for CFS by Kjetil Gundro Brurberg and others.
The comments can be found quickly here (p.113-133)
https://goo.gl/yaH6jR
https://www.dropbox.com/s/koehut6iw2bm9v5/Larun_et_al-2017-The_Cochrane_Library.pdf?dl=0
Many points apply to this piece.
"When is it appropriate to say that patients have recovered? When they are cured of cancer, when their health condition allows them to return to work or when they feel as well as they did before they were sick?"
It is an interesting question. However it is very hard to argue that the revised definition of recovery the PACE Trial investigators published on is anything close to satisfactory. I was a co-author of the paper that discusses this in more detail:
I was also co-author of the rejoinder to the PACE Trial investigators' response:
PACE trial claims of recovery are not justified by the data: A Rejoinder to Sharpe, Chalder, Johnson, Goldsmith and White (2017)
https://www.researchgate.net/publication/315482747_PACE_trial_claims_of_recovery_are_not_justified_by_the_data_A_Rejoinder_to_Sharpe_Chalder_Johnson_Goldsmith_and_White_2017
It is interesting that you bring up the point about employment. Letters to the editor in response to the PACE Trial recovery paper requested such data and other objective data on those the PACE Trial investigators claimed were recovered but the PACE Trial investigators refused to give it:
http://www.meassociation.org.uk/2013/07/pace-trial-letters-and-reply-journal-of-psychological-medicine-august-2013/
Also your own Cochrane review of exercise therapy for CFS did not publish data on employment measures and other objective measures that have been reported in trials that have assessed exercise therapy for CFS.
I raised this point in a comment on your review which can be read here: https://www.dropbox.com/s/koehut6iw2bm9v5/Larun_et_al-2017-The_Cochrane_Library.pdf?dl=0
Clark Ellis
Anyone want to offer me odds on this MentalElf blog ever publishing a piece about PACE that doesn't defend it? I'm not sure I'd take the bet if it was offered, but then Leicester City fans took a punt at 5000/1 not long ago and won, so you never know, I could maybe set a new record of winning from even higher odds. I could certainly use the money since GET treatment made me bed-bound and I had to permanently give up my job.
Catherine Hale
Dear Andre,
You asked me to justify my comments on twitter. I owe you a measured explanation of my throwaway comment about you belonging to an elite of psychiatrists who sneer at patients.
I admit, I only glanced at your website. You may or may not have worked alongside Ben Goldacre, an apologist for PACE by his very silence on the subject. You may or may not move in the same circles as Goldacre, Sharpe, Chalder, White and Wessely. But of course sharing the same stamping ground is not in itself a sufficient cause of the arrogance I accused you of, nor even a necessary one. However, publishing a blog defending PACE when PACE and its proponents have been so thoroughly discredited outside the cosy UK elite is a giveaway that you at least share their values, even if you don't enjoy their patronage.
Those values are that the professionals know best and the patient is not a credible witness to her own condition. Medical knowledge about ME is in its infancy, and yet the PACE researchers unshakably believe they know best about its causes and treatments. The crux of the PACE narrative, and biopsychosocial paradigm in general, is false illness beliefs on the part of patients. CBT and GET used by proponents of BPS model of ME are not the same as that used for cancer and MS. They explicitly impute a cognitive-behavioural model of the illness and aim to reverse the dysfunctional mind/behaviour complex which say they maintains symptoms and functional impairment. For cancer and MS CBT is it used for symptom management, not to reverse the disease itself.
To defend the PACE trial is to assert that false illness beliefs are the cause of ME because that was the explicit premise of the researchers. Which is tantamount to saying that patients are deluded and the professionals know best. To defend the PACE trial is to ignore or dismiss the deep and widespread hurt and anger in the patient community rather than try to understand it.
You say you have learned from two friends with ME. If you would like to go deeper in understanding the basis of the global ME activist movement I would like to give you some pointers. PACE proponents are fond of saying we are driven by a rejection of the stigma of mental illness. Yet there is no evidence that we hold prejudiced views about mental illness, at least no more than the general population. Our anger and hurt comes from the shocking lack of progress in biomedical research for which the lazy BPS paradigm is at least partly to blame. And for a great many of us, it comes from our personal experience of trying CBT and GET in good faith and finding ourselves increasingly disabled and ill as a result, and then of having that experience of deterioration dismissed as another form of false consciousness and negative mindset. My own account of this is here. As I'm sure you know, I'm not alone.
Can you discount patient accounts like mine on the basis they're an unrepresentative minority? Can you discount the evidence of harm from GET from multiple, large scale patient surveys on the basis that it is inferior to professional peer-reviewed science, ignoring the hugely unequal relations of research production in which "evidence" is generated? Can you discount 15,000 signatures from patients gathered in a week in a petition to NICE to review its guidelines to remove the recommendations of CBT and GET in the treatment of ME? Because to defend PACE means to dismiss all of that as worthless, unreliable, inferior evidence.
The ME activist movement is about resistance to the oppression of having our experience discounted as worthless, you could call it resistance against epistemological injustice. What I meant to say is that defending PACE puts you on the side of the oppressors, whoever your chums are. And by defending PACE your website is not cutting through bias and spin but perpetuating it.
This branch of medicine (dealing with presumed "psychosomatic" conditions) is in deep trouble. The modus operandi in this field led to peptic ulcer, asthma, autism, rheumatoid arthritis, some forms of cancer, and many other conditions to be labelled as psychosomatic. Just because a condition isn't understood does not mean that it must somehow be psychosomatic. Real proof that it is must be obtained. In the case of ME/CFS this has never happened. Instead the CBT/GET for CFS proponents were content with wishful thinking and clinical trials that were so poorly designed that even homeopathy would stand a good chance at being proven effective. We see the same thinking and behaviour with other conditions as well, but change is impossible as long as patients are not heard. Being branded unreliable witnesses to our own condition is effectively a form oppression, and we have paid a heavy price for this. It doesn't have to be this way: patients and researchers could collaborate, exchange ideas and go wherever the data leads them. Fortunately we're seeing more of this collaborative rather than oppressive approach in recent years. Norway is leading the way here: this year research funds for ME/CFS were allocated with input from patients and carers.
There's an opportunity here for professionals to distinguish themselves by hearing patients and embracing change rather than trying to resist it.
Lidia Thompson replied:
View October 24, 2017
Well said Catherine.
This article published in the Morning Star on Mon 23rd October 2017, says something similar, also very well. It gets to the heart of what this is actually all about:
"ME Sufferers Being Shamefully Let Down By Professionals."
http://www.morningstaronline.co.uk/a-bd8f-ME-sufferers-being-shamefully-let-down-by-professionals#.We-ml2hSyM_
This debate is becoming unnecessary. PACE will be see for what it is when biomed science reaches conclusions and treatments – that i very much think will be similar to scientific findings in the 1980s!
When Dr Brurberg responded to two of the comments, I thought he was breaking the model of the PACE appologists and actually engaging in rational debate. I have been returning to this thread regularly in the hope that he would get beyond complaining that he has not been understood and get beyond complaining that the JHP have treated him badly to actually responding to the commenters pointing to the errors of fact in his commentary and to the logical and methodological flaws of the original PACE study they raise.
It is very disappointing that the PACE school has no interest in advancing our understanding of ME and its treatment, rather an obsession with promoting a limited treatment package without any scientifically sound basis. It would appear that Dr Brurberg is joining them in promoting PACE without any real intent to understand ME. By posting here Dr Brurberg is seeking to portray himself as the valiant outsider defending the hard done by underdog, the PACE scientists, whereas most patients and an increasing number of international scientists are objecting to the PACE bias of the UK medical establishment that has effectively being holding back ME research and treatment in the UK and some other countries and promoting downright bad science.
I ought not to be surprised by this as the UK PACE appologists have almost made careers based on teaching other researchers how to devalue and ignore those horrid ungrateful ME patients and spent tens of thousands of pounds trying to keep their data out of the hands of researchers that disagree with them. It is sad if this obfuscation and avoidance of rational debate is spreading to other countries. PACE is taught in some American universities as an example of how not to undertake research, but unfortunately it is still being misused to guide treatment, service provision and benefits in the UK and a few other countries. Dr Brurberg complains he has not been given a fair hearing, but his selective response so far to comments here would suggest he is doing exactly that to the commenters who disagree with him.
Regardless of whether the JHP have treated him fairly or not the issues raised by commenters deserve a considered response, though unfortunately if Dr Brurberg is learning from the PACE school he will regarded us as deliberately vexatious and further examples of those horrid patients and their advocates that want to suppress 'true' science.
I hope I am not doing Dr Brurberg a disservice and that in fact he is thinking through the issues raised here and planning a well thought out response. I hope this is the case, but I am not optimistic.
Statements from IOM report, 2015:
"ME/CFS is a serious, chronic, complex, multisystem disease that frequently and dramatically limits the activities of affected patients."
"it is 'real', not psychogenic."
"Exertion of any sort can adversely affect patients in many organ systems."
As for the PACE Trial, this article sums up the fiasco fairly well:
PACE-Gate: The Making of a Medical Scandal
by James C Coyne July 29, 2017
https://www.coyneoftherealm.com/blogs/news/pace-gate-the-making-of-a-medical-scandal
Today sees the publication of the Journal issue that Dr Brurberg feels he was so unjustly excluded. Apparently, one or more unnamed PACE supporters nearly succeeded in blocking its publication. Fortunately it is going ahead, see
http://www.meassociation.org.uk/2017/07/the-pace-trial-the-making-of-a-medical-scandal-29-july-2017/
For anyone who wants to know more about real scientists and their research on ME/CFS, watch the OMF symposium.
https://www.youtube.com/watch?v=s7bBMXQSmuM
The difference being that CBT for cancer and MS is very different for CBT for ME/CFS. Cancer patients are not told they have false illness beliefs, nor told they are ill because it benefits them as they are attention seeking and perfectionists. GET May be useful for depression related fatigue, but causes harm to patients with PEM, a hallmark symptom of ME/CFS is PEM. Ignoring PEM is a reckless abuse of patients and according to the ME Assosciation petition over the use of GET in the NICE guideline, over 15,000 patients cited being harmed by GET. If this has been a trial for a new medicine, it would have been swiftly withdrawn due to patient harm. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680051/
https://translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-12-104