PACE Trial and PACE Trial Protocol

[Dolphin]

New thread: PACE Trial - letters that were not accepted by the Lancet

http://forums.phoenixrising.me/show...-letters-that-were-not-accepted-by-the-Lancet

15 letters have now been posted.

25 letters from 20 individuals/groups now up.

 

[Sean]

"you have to be cruel to be kind"

One of the more insidious and damaging ideas to have to deal with.

 

[biophile]

Catching up

oceanblue posts on [Exercise and effect on walking: PACE CFS similar to MS]

Good find!

[ancientdaze on biophile's spelling error of 6MWD as "6WMD"]: For a moment, I thought you meant Weapons of Mass Disinformation.

Ha! I often make that same mistake offline as well.

oceanblue wrote: Truncated scaling is dodgy for a non-specialist audience eg in a newspaper, but is widely accepted in scientific journals to save space, so long as the break in the axis is clearly shown, as it was in this case. So in this particular instance I'm pretty sure the authors were merely following standard practice rather than trying to decieve. The deception they managed in other ways.

Agreed, although I wouldn't be surprised if the medical audience fell for it anyway. ME/CFS is the twilight zone afterall.

Dolphin wrote: People should see the need for it - it's "hardly rocking science" that in a medical setting, one might one such information to see who prescribe a therapy too. [...] However, this may be as unsatisfactory as their claim there is no difference for those with ME (London criteria) or International critera, CFS.

Modified versions of these criteria of course.

Graham wrote: The "deception" that really bothers me is that the study focused on snapshots of the distribution of scores in the groups rather than the distribution of improvements in scores. [...] With all that time spent in Specialist Medical Care, they must have pretty thorough information about each patient: I would have spent as long as it takes to try to use that information to determine some sort of way of defining who exactly is helped by CBT/GET and who is harmed (and looking at the distributions, there must have been a very small minority that did benefit to a quite reasonable extent).

ancientdaze wrote: There is an issue here which we cannot address without a better idea of the raw data used to produce group measures. If a defective definition of the illness caused them to include a few subjects who did not have ME/CFS, these would naturally show large gains over the course of a year, possibly without any treatment at all. Including a small percentage of these, and dropping a small number of subjects who were too ill the complete the trial, could produce all the change seen. Of course, if this happened, it would be easy to tell what was going on if you looked at raw data. Therefore, I don't expect to see data which addresses such questions.

Good point.

ancientdaze wrote: Researchers are just as capable of self-deception as patients. Published work on confirmation bias is abundant.

Ever get the impression that some of those who work in "psychological medicine" think they are somehow above or particularly immune to confirmation bias compared to everyone else?

Dolphin wrote: This trial hasn't shown that if a person instead didn't reduce activity, that that would lead to no "serious adverse events or reactions".

Exactly. We are being sold "paced exercise therapy" (PET) as GET but we will be expected to undergo literal GET as a result of the trial.

oceanblue wrote: It would also have been very interesting to see how patient's attributed the cause of their serious events as well as the 'independent' assessor (not that patient attributions would have any basis in reality...).

Indeed.

oceanblue wrote: [105 CBT/GET sessions = 1 patient marginally improved]

Another good point. For every 7 to 8 patients who are subjected to futile attempts at CBT/GET, a single patient matching Oxford criteria CFS will subjectively report a small improvement. And people wonder we aren't celebrating?

wdb wrote: I noticed a lot of these letters describe the 6MWD as an objective test but is it truly objective in the way that for example a machine measured specific blood count would be ? There must be factors such as reckless determination, willingness to risk relapse, or blind denial of ramifications that could affect the result independently of any actual objective change.

Good point.

oceanblue wrote:

[Michael Sharpe gives more honest appraisal of PACE results in ABC radio interview]

"Well, Richard, on the basis of what Michael Sharpe has just said, the CBT model is clearly wrong. The rest of Horton's comments are in similar vein."

Yes, but towards the beginning of the very same transcript, Sharpe also says: "Two of the treatments did very much better than two of the other treatments."

urbantravels wrote: Watch the presentation by Christopher Snell of the Pacific Fatigue Lab from the State of the Knowledge conference - he's on toward the end of Day 1. Toward the end of his presentation he discusses PACE a little bit. He is pretty scathing about how manipulable/influenceable the 6 minute walk test is (I forget the exact word he used, even though I just rewatched it yesterday.) Dr. Snell's conclusion: Metabolic data (i.e., the kind of data the PFL collects in its exercise test) or GTFO.

Interesting, will do.

ancientdaze wrote: There's still an elephant in the room, statistically. If 31% of participants did not take both 6MWT, you have a selection effect large enough to explain the entire improvement in the GET group, (even though I do not believe this is clinically significant.) This still ignores the 21 meters which appear to be due to retest familiarity. Competent researchers intending to use the 6MWT would have had three runs: one for practice, one for initial values and one for final values. The carelessness here indicates they weren't very concerned with objective data, which fits with the unused data from Actometers. An alternative interpretation is that patients were sicker than believed, and the sickest were not able to complete both 6MWT. If you deny both of these, we can get into conspiracy theories. Anyone care to present these alternatives to those who ran PACE? The bottom line from this trial comes down to a particularly weak endorsement: few of those participating ended up in hospital. It's a pity they didn't have a r eal control group, so we could judge that aspect fairly. My own view is that there is enough self-deception and incompetence already apparent to explain all results. The hard bit is explaining the press release, unless this is standard scientific spin control to avoid charges of p*ssing away 5M pounds. If you don't believe this happens, consider this SNAFU. One of the critics quoted in that article, Michael Griffin, was allegedly in charge of NASA!

I agree. The only potential problem I can see with this important argument is that there was a lower than usual participation in the 6MWT in all 4 groups, and that an increase in retest familiarity could have affected all 4 groups as well.

APT (n=111/70%) | CBT (n=123/76%) | GET (n=110/69%) | SMC (n=118/74%)

No surprise the APT group didn't do so well when they were encouraged to avoid exacerbations and stay under a 70% limit. However, we can see that the GET group had 8 less participants than the SMC group.

Unless of course PACE did something dodgy, such as: some groups had a much lower participation than others so they cherry picked some scores out from other groups so the scores would be roughly comparable.

This is just another aspect of PACE which they could have put as much spin on genuine data as possible and then leave the rest up to obscurity ie tell us nothing about those who didn't do the 6MWT and can always claim that the low participation rates affected all 4 groups so should be comparable.

[BMJ coverage of the PACE Trial] (thanks Dolphin)

"Less than a third of patients were cured by either treatment (30% (44/148) after CBT and 28% (43/154) after graded exercise therapy)."

This is appalling. It is understandable that a typical news article swept up in the hype can get it wrong, but a medical journal explicitly using the word "cure", it means incompetence.

 

[oceanblue]

oceanblue wrote:
[Michael Sharpe gives more honest appraisal of PACE results in ABC radio interview]
"Well, Richard, on the basis of what Michael Sharpe has just said, the CBT model is clearly wrong. The rest of Horton's comments are in similar vein."

Yes, but towards the beginning of the very same transcript, Sharpe also says: "Two of the treatments did very much better than two of the other treatments."

He did, but when he discussed the results in detail he said "So the differences we're looking at here are clinically useful, but they're not actually enormous." and "We have a number needed to treat; I think it's about seven to get a clinically important treatment benefit with CBT and GET" [it's 8 for GET]. These comments surely carry more weight as they are specific and scientific - and undermine Horton's argument. It would be a pity to look a gift horse in the mouth.

Thanks for your other kind comments.

 

[Bob]

Invest in ME have sent an open letter to Dr Richard Horton, the editor of The Lancet, along with an invitation to the Invest in ME conference, in response to his Australian radio broadcast...
http://www.investinme.org/IIME Letter 2011-04 Lancet.htm

 

[Bob]

Prof Malcolm Hooper's complaint to the editor of The Lancet re The PACE Trial


It looks like Prof Malcolm Hooper has now published his critical analysis of the PACE Trial...


"REPORT: COMPLAINT TO THE RELEVANT EXECUTIVE EDITOR OF THE LANCET ABOUT THE PACE TRIAL ARTICLES PUBLISHED BY THE LANCET"
http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.htm

Download it as a Word doc format here:
http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.doc





And here's a bit of an introduction and background to the complaint, by Margaret Williams, that's interesting to read:

"The Media and ME"
http://www.meactionuk.org.uk/The-Media-and-ME.htm

Extract from "The Media and ME":

The Media and ME

...

These flaws and errors have been identified in a detailed complaint/statistical analysis sent by Professor Malcolm Hooper to The Lancet on 28th March 2011, upon which The Lancet has asked Professor Peter White to comment (a response with which Professor White has apparently not complied within the time allotted for its receipt by The Lancet).

It is understood that under the Elsevier complaints policy, Professor Hooper will be asked to respond to Professor Whites reply when it is received by The Lancet; it is also understood that the PACE Trial article was to be sent for re-review by different reviewers and statisticians whilst The Lancet was awaiting Professor Whites comments on Professor Hoopers complaint.

Professor Hoopers analysis will shortly be placed in the public domain; he had agreed with The Lancet to withhold his complaint from publication during the time allotted by The Lancet to Professor White to respond to it, but this agreed time limit has now expired.

...

http://www.meactionuk.org.uk/The-Media-and-ME.htm

 

[anciendaze]

...I agree. The only potential problem I can see with this important argument is that there was a lower than usual participation in the 6MWT in all 4 groups, and that an increase in retest familiarity could have affected all 4 groups as well.

I think we have good reason to attribute a 20 meter improvement to retest familiarity or selection effects due to patients who were included in the trial, but did not take both 6MWT. I also want to point out that the highest percentage of those not taking both 6MWT was in the group with the highest gains. This is a strong hint that negative selection of those who did not take tests played a significant role in improvements.

No surprise the APT group didn't do so well when they were encouraged to avoid exacerbations and stay under a 70% limit.

Where they came up with this 70% limit is a mystery. I exceed 70% every time I stand up. If I am not careful, this leads to syncope. In one case, emergency medical personnel reported that I had a seizure. This was later reduced to "unexplained loss of consciousness". Had such an event occurred in PACE we could expect those careful guardians of our well-being to report this was not a serious adverse event, since I left hospital without diagnosis of permanent damage.

I've been living with this for decades, so I would be unlikely to change my opinions due to a year of jawboning by people who don't have this illness. Here we should take note that the mean length of illness in PACE participants was two years.

The psychosocial model of the illness would mark me as a terminal case of learned helplessness. This has an advantage of excluding those with much experience with the disease from cohorts where you can expect significant results. The only way to falsify such an hypothesis is to follow patients for decades to see if gains last. (And, I'm not even sure they couldn't talk their way out of failure there.) This is exactly the delay in changing treatment recommendations those running this trial want.

What we have in the detailed results is proof that a substantial percentage, (perhaps 30% or 40% or even 60%, nobody is sure,) received no benefit from a year of treatment -- even when researchers were allowed to define the disease to exclude those they didn't want to treat. Translated into numbers in the general population this is huge. This simple, obvious interpretation is "we don't know what's wrong with this group, and we don't know how to treat it."

 

[Dolphin]

Exactly. We are being sold "paced exercise therapy" (PET) as GET but we will be expected to undergo literal GET as a result of the trial.

Well put.

Incidentally (not exactly the same point), I came across one PACE Trial participant saying they were counting a few minutes housework as their exercise - clearly not what professionals, etc. are told is the therapy.

 

[Bob]

We are also being sold prescriptive APT as a form of pacing, and will be denied pacing as an option for treatment as a result of the trial.

 

[Snow Leopard]

The reality is that unless they objectively measure activity levels, they cannot exclude the possibility that the GET patients might merely be engaging in activity substitution as Dr Friedberg found in one of his case studies.

 

[Snow Leopard]

This thread is getting way too long (I haven't read half of it), is it worth starting a new one with more focused discussion?

I also posted this in the ABC radio/PACE thread:

I think we need to leverage (a) the importance of actometer results and (b) long term followups (eg 2 or even 5 years after the conclusion of the intervention).

Since baseline data was gathered, there is no scientific reason why this cannot be done.

I suggest this is something to push for.

 

[Dolphin]

This thread is getting way too long (I haven't read half of it), is it worth starting a new one with more focused discussion?

I also posted this in the ABC radio/PACE thread:

I think we need to leverage (a) the importance of actometer results and (b) long term followups (eg 2 or even 5 years after the conclusion of the intervention).

Since baseline data was gathered, there is no scientific reason why this cannot be done.

I suggest this is something to push for.

They got some sort of permission for long-term follow-up. What data, if anything, we see may depend on what suits them.

I remember reading one study and the authors mentioned they were doing a long-term follow-up; this was years later so I asked about it: the PI said a Master's student (IIRC) had done her Master's on it, the PI encouraged the Master's student to publish but it hadn't happened. Would need to double-check. Anyway pretty weak. There has been a lack of long-term follow-up in ME/CFS.

I have asked for actometers to be used. However unfortunately at this stage, time is ticking by fast e.g. the first people started around 2005 (?) so it's a long-time since they had therapy.

 

[oceanblue]

This thread is getting way too long (I haven't read half of it), is it worth starting a new one with more focused discussion?

Any suggestion for what that focus should be? Or maybe just a new thread from, say, 1st May would be less off-putting than this current monster?

 

[Esther12]

This thread is an unwieldy monster... but the discussion's been pretty focuse. There have just been a lot of points to be made. I'm sure we could condense it dramatically now that we have a better idea what's going on (a lot of the discussion was exploratory) - but that's a massive task. I want to do it... but it's very tempting to hope someone else will!

 

[Mark]

Trawling through the thread may not be the way forward, the key points are all there in people's heads anyway so you'd probably get there by starting from scratch with a blank sheet of paper, lising the main points, then referring to the thread for the details. But if you do want to trawl the thread, many hands make light work: share out sections, 100 posts each for 9 people, with clear agenda on what you want to pull out. Put all that output into categories then condense again...

I had a think the other day about this and sketched out a few of my views on the kind of presentation we need that ends up lacking. I'm a big believer in the value of "Don't make me think" approach to presentation. Just because doctors are smart doesn't mean that messages don't get across to them easier if things are spelled out in a clear and user-friendly way. So: here are my ideas about what's needed as a final output, and a rough sketch of the sort of format I have in mind, as an example. Kep point is making it accessible at every level: headlines, super-readable summaries, links out to greater detail, and full quotes and references to back it up:

Core requirements
(a) aimed at the general public to grab their attention with sound-bite headlines on all points,
(b) very easily laid out for people to read easily,
(c) presenting a devastating case against PACE, (and similarly for UK ME underfunding etc).

Example: (the key here is format not the content as such):

1. PACE STUDIED ONLY A SUBSET OF ME/CFS PATIENTS: THE RESULTS DON'T APPLY TO THOSE WHO WERE EXCLUDED
PACE only studied a restricted subset of people who were referred as ME/CFS patients - less than a quarter of those originally referred - and did not include bedbound patients, those most seriously ill, or those with the hallmark neurological signs of ME. Yet its findings are being generalised to all people with "CFS/ME" - and claimed as evidence that the treatment is safe for them all. Half of those referred were found to 'not really have ME/CFS' because they had some other medical condition: such high levels of apparent misdiagnoses of ME/CFS would seem to be an important finding of the study.
(See _here_ for links and references for more detail on this)

2. THE AUTHORS ABANDONED OBJECTIVE PHYSICAL MEASURES OF FATIGUE MIDWAY THROUGH THE STUDY
PACE changed the study protocol partway through the study, moving the goalposts in several ways that helped the authors reach the conclusions they wanted. One of the most flagrant examples of this was the abandoning of the use of actometers - small devices for measuring day-to-day physical activity. These were abandoned shortly after a separate CBT/GET study found that, although patients claimed to have increased physical activity on the questionnaires, the actometers showed that in reality their activity had DEcreased slightly. The authors claimed that they had dropped the use of actometers - small wristwatch sized devices - "because it was unfair to the patients to expect them to wear them". Unsurprisingly, the patient community views that claim with considerable scepticism.
(See _here_ for links and references for more detail on this)

3. THE AUTHORS CHANGED THE DEFINITION OF 'NORMAL' FUNCTIONING MIDWAY THROUGH - RE-DEFINING 'NORMAL' TO MEAN FATIGUED PEOPLE VISITING DOCTORS' SURGERIES

etc...etc...etc

There should be about 10 fundamental points I reckon, with subsections under some of the main sections. Including:

- Conflicts of interest
- Changes to the protocol
- Statistical manipulation
- Unavailability of key data
- Unreliability of self-report questionnaires

There's two parts really as well: flaws in the trial, and inaccuracies in the media reporting. For the latter problem, a big list of 'positive' quotes from the paper itself would be useful, because they were actually obliged to admit that the effect was small, full recoveries weren't achieved, and real medical research is needed...etc...so those quotes can be used by us in fact with relation to media reporting: "The authors themselves say this; your report says that...". Main issues I see there are:

- Small size of improvements achieved
- Large number who showed no benefit

Ultimately I would like to see an encyclopaedic set of web pages about PACE - a dedicated website perhaps - in a format similar to the above: 100% rigorous and indisputable (peer-reviewed by us all), with links to more details, references, etc etc.

The issues are so complex and often so subtle - though here many are blatant - that there's a need for this "3-tier" approach to presentation: this is the problem Prof Hooper faces of course, the sheer quantity and maze-like obfuscation of the matter - and his document is of course a great source as well.

 

[Angela Kennedy]

Adding to this thread for continuity:

COMPLAINT TO THE EDITOR OF THE LANCET REGARDING THE PACE TRIAL

PERMISSION TO REPOST

I have today (Monday 25th April) emailed the editor of the Lancet, Richard Horton, with my own complaint regarding the PACE trial as below

Angela Kennedy

----------------------------------------

Dear Doctor Horton

Further to my email correspondence with one of your colleagues, Zoe Mullan, about the PACE trial, I am writing to you to complain, formally, about the article: White PD, Goldsmith KA, Johnson AL, et al. Comparison of adaptive pacing therapy, cognitive behaviour therapy,

graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet 2011; 377: 823-836.

The PACE trial was subject to a large amount of concern and objection by advocates for those diagnosed with ME or CFS, from the beginning of the study in 2004 and throughout its course. I was one of those who outlined specific concerns at the beginning of the trial: and various concerns were also outlined in response to the publication of the protocol mid-trial. For evidence of this please see my own and others comments at:

http://www.biomedcentral.com/1471-2377/7/6/comments/comments

I am writing primarily as the mother and long-term advocate of a child (now a woman) diagnosed at 13 with ME/CFS, and who has various objective, medically substantiated organic impairments (especially neurological and cardiovascular) which have led to severe disability. If subjected to PACE-type CBT and GET, she would be at serious risk of further harm.

There remain a large number of very serious flaws, problems and discrepancies in this whole study, including the published article in the Lancet. I am writing to reiterate the many substantive and valid concerns raised by Professor Malcolm Hooper in his complaint to you about this article and the trial itself, available here:

http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.htm

http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.doc

I am also aware that a large number of valid and substantive criticisms of the trial have been made in letter form to the Lancet and have been rejected for publication.

In addition to the above concerns, I am specifically gravely concerned about the dangers to patients caused by the unsafe claims that Cognitive Behavioural Therapy of the type advocated by White et al, and Graded Exercise Therapy, are safe treatments for people diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, claims propounded both within the PACE article itself, and the accompanying editorial. This has led to similar unsound claims being made elsewhere. The potential adverse ramifications for patients of these unsound claims are particularly serious, and therefore those claims should not have been made.

Bleijenberg and Knoop, in their Lancet editorial accompanying the publication of the PACE article, claim:

Concerns about the safety of cognitive behaviour therapy and graded exercise therapy have been raised more than once by patients advocacy groups. Few patients receiving cognitive behaviour therapy or graded exercise therapy in the PACE trial had serious adverse reactions and no more than those receiving adaptive pacing therapy or standard medical care, which for cognitive behavioural therapy has already been shownThis finding is important and should be communicated to patients to dispel unnecessary concerns about the possible detrimental effects of cognitive behaviour therapy and graded exercise therapy, which will hopefully be a useful reminder of the potential positive effects of both interventions.

The PACE article itself states:

"Trial findings show cognitive behaviour therapy (CBT) and graded exercise therapy (GET) can be effective treatments for chronic fatigue syndrome, but patients organisations have reported that these treatments can be harmful and favour pacing and specialist health care. We aimed to assess effectiveness and safety of all four treatments."

The same article concludes:

"Findings from the PACE trial suggest that individually delivered CBT and GET, when added to SMC, are more effective and as safe as APT added to SMC or SMC alone. Patients attending secondary care with chronic fatigue syndrome should be offered individual CBT or GET, alongside SMC.

Other parties have repeated these unsafe claims, informed by the PACE trial. One example of a newspaper article is that in the Daily Mail, on 18th February 2011, which claims:

Got ME? Fatigued patients who go out and exercise have best hope of recovery, finds study.

A press release from the Science Media Centre about the trial included various unsound claims of safety from doctors. Alistair Miller, for example, stated:

"It provides convincing evidence that GET and CBT are safe and effective and should be widely available for our patients with CFS/ME.

Derick Wade, as another example, claimed that the trial:

"...confirms the effectiveness of two treatments, and their safety. The study suggests that everyone with the condition should be offered the treatment, and every patient who wishes to be helped should be willing to try one or both of the treatments.

In addition to the claim of safety of CBT and GET, Wade's comment also indicates that patients may be regarded as recalcitrant (for example, in a context of welfare support or continued medical support) should they, quite rationally, dare refuse to 'try' treatments that actually may be dangerous.

The fundamental problem that needs to be addressed is that the evidence available shows that, contrary to the above claims, the PACE trial did not adequately assess, or even address, safety of CBT and GET, and this study did not disprove patients and doctors' valid and substantive concerns regarding the dangers of CBT and GET. One major discrepancy of the PACE trial and the resulting article was the failure to address the biomedical evidence available detailing serious organic physiological dysfunction in patients who receive a 'CFS' or 'ME' diagnosis. Another is the inadequate treatment of adverse outcomes within the trial. This is discussed in more detail in Professor Hooper's document as detailed above.

I wish to raise specific concerns about the patient cohort. Evidence indicates that research cohorts for CFS or CFS/ME appear to be obtained (by those promoting psychogenic explanations for these conditions) by excluding patients with signs and symptoms (especially neurological) found in Myalgic Encephalomyelitis case descriptions, or indeed other organic diseases (the alternative diagnoses). The PACE trial used, not just one case criteria to exclude

patients with symptoms and signs of organic disease from the trial, but three: Oxford (Sharpe et al, 1991); Reeves et al (2003), and those from the NICE guidelines (see White et al, 2011: 2).

Of 3158 patients who had been referred to six specialist chronic fatigue syndrome clinics in the UK National Health Service (White et al, 2011: 2), 1187 patients (over a third) were actually excluded because they did not actually meet Oxford criteria for CFS. Confusingly, no figures are given for those meeting Reeves et al (2003) and NICE exclusionary criteria, though these are claimed as part of the exclusion process. This is possibly because the Oxford criteria themselves efficiently exclude those with signs and symptoms of neurological myalgic encephalomyelitis, to the point that the Reeves and NICE exclusionary criteria may well have been superfluous.

There are similarities of symptoms and signs of neurological dysfunction found in specific case descriptions of myalgic encephalomyelitis (for example, Ramsay, 1988), or ME/CFS (as defined by Carruthers et al, 2003), with other neurological conditions, for just one example, those found in Multiple Sclerosis (see, for example, Poser 2000). Therefore, to have included patients with neurological symptoms and/or signs might have meant there was a risk of other neurological conditions (such as Multiple Sclerosis) being involved in the trial. Indeed, in his response to me on the biomedcentral site, Peter White discusses the need to keep people with other neurological conditions out of the trial. But, crucially, the key problem here is that, from the evidence available (some of which is detailed by Professor Hooper), Professor White and his colleagues do not appear to believe 'ME' is a neurological condition in the first place, despite the acceptance of this by the World Health Organisation and British agencies, and despite the evidence available to support this, and therefore seem unable to acknowledge that at least some people given an ME or CFS diagnosis have organic neurological and other deficits. It seems therefore likely that ME/CFS patients with signs and symptoms of neurological (and indeed other organic) dysfunction were actively excluded from the PACE trial.

Ironically, if this premise is accurate, White et al cannot have substantiated their claims for the safety and efficacy of CBT/GET for patients they claim such treatments are safe and efficacious, those given an ME or CFS diagnosis who suffer physiological impairments including neurological deficits. It needs to be noted that the PACE article actually claims the results:

can be generalised to patients who meet alternative diagnostic criteria for chronic fatigue syndrome and myalgic encephalomyelitis but only if fatigue is their main symptom (citing the London criteria and Reeves et al 2003 as the alternative diagnostic criteria). This is a confusing statement, bearing in mind that: the London Criteria used in PACE were not actually that as referenced by them (as the documentation from the PACE trial protocol shows); the Reeves et al criteria were supposed to have been used by them within the trial itself (so the question arises, why are they alternative?); and their conclusions, and that of Bleijenberg and Knoop and others, presents a blanket claim of safety and efficacy for all people given a diagnosis of ME or CFS, contradicting this statement about only if fatigue is their main symptom.

Indeed, it is notable that White et al, from the beginning of the trial and throughout, refused to use the criteria of Carruthers et al (2003) to include people with symptoms (and possibly signs) of neurological dysfunction, although they used their own (specifically customised and therefore different) version of a set of criteria claimed to identify ME (the London criteria), already controversial due to lack of peer reviewed publication, uncertainty in authorship, and the existence of different versions. Indeed, as is evident from the PACE Trial protocol, the specifically customized PACE version of the London criteria for ME bore close similarities to the Oxford criteria for CFS, and were fundamentally different to the Carruthers et al criteria (2003).

That so many patients (nearly a third), of whom had been referred to a specialist chronic fatigue syndrome unit by their GP, were actually excluded from the CFS diagnosis favoured by these authors, is extremely important, and leads to the question: what happens to such patients? When the patient exclusion process of another project (the negative XMRV study by Erlwein et al, 2009) was clarified by co-authors (Wessely et al, 2010), some clinical patients who had attended chronic fatigue/CFS clinics commented in response that they had not been investigated thoroughly in the way the research cohorts appeared to be (ironically in order to exclude organic disease), either at the clinic or by their GP. Another study by Newton et al (2010) found that 40% of patients referred to a chronic fatigue syndrome unit did not have CFS, though, crucially, Newton was including, as CFS patients, those with specific physiological conditions such as positional orthostatic tachycardia syndrome (POTS), which are associated with neurological dysfunction (Carruthers et al, 2003). If these patients had been also excluded from a diagnosis of CFS (which, according to the Oxford criteria and indeed the Reeves et al criteria, they should), the amount of patients referred to British chronic fatigue syndrome units (or, often, chronic fatigue units), meeting the Oxford criteria for CFS and having no exclusionary conditions that suggest organic dysfunction, would appear to be very small indeed. But even patients excluded under the rubric of the Oxford criteria from research, will now be exhorted to try CBT and/or GET in a clinical context, because of the unsafe claims of the PACE trial.

Another major discrepancy in the PACE trial that I wish to specifically highlight here is that one of the treatments, Adaptive Pacing Therapy, bore no resemblance to the strategy of pacing, specifically adopted by ME patients and reported as being helpful by them in charity surveys. Pacing as reported in these surveys is merely an autonomous flexible management strategy utilised by patients with ME in order to cope with the limitations of the illness, like sufferers of other chronic impairments. The PACE trials Adaptive Pacing Therapy was not autonomous, being therapist led, and imposed a regime upon the patient similar to the GET treatment. This has specific iatrogenic potential in that, informed by the claims of PACE, patients may be told by health care professionals that an autonomous, flexible self-management strategy that is common in patients with chronic impairments, that has been found to be useful in ME/CFS, must not be practised, on the incorrect findings of a trial that did not even study the correct type of 'pacing' in the first place.

In light of the extremely complex and serious problems of confounding inherent in this trial, it is of serious issue that unsafe claims of safety and efficacy of CBT/GET as treatments for ME or CFS were made by the PACE authors and supporters, to the point that iatrogenic harm could be caused to patients because of a resulting lack of understanding, by medics and ancillary staff, misinformed by such unsafe claims, of both the neurological and other physiological impairments in at least some patients given such diagnoses, and the abnormal physiological response to exertion that appears to be a key feature in those patients.

I also draw your attention to your colleague Zoe Mullan's comment to me in our email correspondence: "We were not aware of any objections to this study". I am very concerned about this as objections to the PACE trial have been publicly mounted, and indeed have been responded to (though in eventuality, not satisfactorily) by authors of the trial, some years prior to publication.

At the very least, a much more detailed discussion of limitations to this study should have been undertaken that took into account the concerns that were raised. In the circumstances and to ensure patient safety, I now believe that the article should be retracted, and the claims that CBT and GET have been found to be safe in ME and/or CFS should be publicly corrected. I must ask that you keep to your promise that we will invite the critics to submit versions of their criticisms for publication and we will try as best as we can to conduct a reasonable scientific debate about this paper made by you on the ABC radio programme 'The Health Report'. I consider myself as one of those critics. Indeed, I believe a full and public good faith investigation of my own and others complaints need to be undertaken by you and other parties, as appropriate.

In addition, I believe there should be an unreserved public apology issued to all the ME community and their advocates who have raised legitimate and substantive concerns, in various ways, about the problems in the PACE trial, for the prejudicial misrepresentation of their concerns and motivations, made by you on the ABC radio programme 'The Health Report', in which you made the following comments:

http://www.abc.net.au/rn/healthreport/stories/2011/3192571.htm

"...the criticisms about this study are a mirage, they obscure the fact that what the investigators did scrupulously was to look at chronic fatigue syndrome from an utterly impartial perspective."

"Not this kind of orchestrated response trying to undermine the credibility of the study from patient groups but also the credibility of the investigators and that's what I think is one of the other alarming aspects of this. This isn't a purely scientific debate; this is going to the heart of the integrity of the scientists who conducted this study."

"...indeed in a few examples of allegations have been made to professional authorities, the General Medical Council here in the UK about the work of these scientists on the basis of the flimsiest and most unfair allegations. And indeed the study costs $4 million pounds to undertake but the allegations and the freedom of information requests and the legal fees that have been wrapped up over the years because of these vexatious claims has added another 750,000 pounds of taxpayers' money to the conduct of this study."

"Indeed, and I think this is where one sees a real fracture in the patient community. One is seeing a very substantial number of patients very willing to engage in this study, desperate to get good evidence on which to base their future treatment but one sees a fairly small, but highly organised, very vocal and very damaging group of individuals who have I would say actually hijacked this agenda and distorted the debate so that it actually harms the overwhelming majority of patients."

"Well what we're doing right now is waiting for the formal response from the authors to this 43 page attack on their integrity and the study and the request for a retraction. We plan to publish their response to that attack, we will invite the critics to submit versions of their criticisms for publication and we will try as best as we can to conduct a reasonable scientific debate about this paper. This will be a test I think of this particular section of the patient community to engage in a proper scientific discussion."

These prejudicial comments should also be retracted. They are inappropriate and inaccurate, and sadly indicate a possible bad faith on your part from the offset, and this is an unusual and extremely worrying response from the editor of a key medical journal to the reasonable concerns that have been raised, in good faith, by a vulnerable patient community and others supporting them. I cannot emphasise enough that the concerns related by myself and others relate specifically to the risks to safety of patients, and our concern to prevent those: this is the motivation for my own actions here.

In addition, please note that I am, here, formally, repeating my request, made to Zoe Mullan initially, that peer review documentation be made accessible to me under the Freedom of Information Act. I understand that the usual procedure under this Act applies. I am concerned that no response has been given to my original request, made in early March.

Please be aware that, in the interests of transparency and accountability, I will be publicising this email, and I may publish the responses I receive.

Yours sincerely

Angela Kennedy

 

[Dolphin]

2 responses in Dutch

I wrote to somebody who I thought might have sent in a letter to the Lancet.

He directed me to the following which may be of interest to people who can speak Dutch.

The first one is a statement by De Steungroep ME en Arbeidsongeschiktheid and De ME/CVS-Stichting Nederland

http://www.steungroep.nl/index.php/...-kloof-tussen-wetenschap-en-patientervaringen

25 feb 2011: Behandeling van ME/CVS; KLOOF TUSSEN WETENSCHAP EN PATINTERVARINGEN




Hilversum/Groningen, 25 februari 2011



Behandeling van ME/CVS

KLOOF TUSSEN WETENSCHAP EN PATINTERVARINGEN



De ME/CVS-Stichting Nederland en de Steungroep ME en Arbeidsongeschiktheid constateren dat de stelling dat Cognitieve Gedragstherapie (CGT) en Graded Exercise Therapy (GET) veilige en effectieve behandelmethodes zijn voor mensen met het Chronisch Vermoeidheid Syndroom (CVS), ingaat tegen de ervaringen van ME/CVS-patinten zelf en ander onderzoek naar behandelmethoden. Zij vrezen dat de publicatie hierover in het Britse blad The Lancet van 18 februari 2011 bijdraagt aan een eenzijdige en daarmee onjuiste beeldvorming over de ziekte en het voor patinten nog moeilijker zal maken om een voor hen passende behandeling te vinden. Beide patintenorganisaties zijn van mening dat de complexiteit van de ziekte en stand van de wetenschap het op dit moment niet rechtvaardigen om in de klinische praktijk n uniforme behandeling toe te passen, die vooral op psycho-sociaal onderzoek is gebaseerd. Zij pleiten voor meer biomedisch onderzoek naar ME/CVS; ook in Nederland.



Niet representatief

De patinten voor het onderzoek zijn geselecteerd op basis van zeer ruime criteria. Uit eerder onderzoek is bekend dat door deze criteria veel patinten worden geselecteerd, die (ook) een psychiatrische aandoening hebben. In de Britse studie blijkt dat bij bijna de helft van de patinten het geval. Het is algemeen bekend dat (chronische) vermoeidheid een veelvoorkomend symptoom is bij psychiatrische aandoeningen. Omdat verder als voorwaarde werd gesteld dat patinten konden reizen naar de plaats waar de therapie werd gegeven werden ernstig zieke ME/CVS-patinten uitgesloten van het onderzoek. Er kan dus gesteld worden dat de onderzochte groep niet representatief was voor de totale groep van ME/CVS-patinten.



Matige resultaten

Er is binnen het Britse onderzoek vooral gekeken naar de effecten van een aantal verschillende therapien op vermoeidheid en fysiek functioneren. Objectieve maten voor bijvoorbeeld het activiteitenniveau van de patinten zijn hierbij niet gebruikt. Bovendien zijn de resultaten van CGT en GET volgens de onderzoekers zelf slechts matig. Meer dan de helft van de patinten had geen baat bij deze behandelingen. De onderzoekers vinden verder onderzoek naar effectievere behandelmethoden dan ook noodzakelijk.



Eigen ervaringen patinten

Uit twaalf enqutes onder in totaal enkele duizenden patinten wereldwijd blijken CGT en GET juist slechter te scoren dan de meeste andere behandelopties (1). Een aanzienlijk deel meldt zelfs negatieve effecten van deze methoden.

Een omgekeerd beeld is te vinden bij pacing (2). Patinten zelf melden met deze strategie juist goede ervaringen. De in het Britse onderzoek gebruikte vorm van pacing, zogenaamde adaptive pacing therapy, wijkt echter sterk af van wat patinten zelf hieronder verstaan (3).



ME/CVS: een complexe biomedische aandoening

Meer dan 4000 wetenschappelijk gepubliceerde artikelen over ME/CVS wijzen naar een biomedische oorzaak en ziektemechanisme. Bij gericht medisch onderzoek van ME/CVS-patinten worden vele lichamelijke afwijkingen gevonden. Recent medisch biologisch onderzoek legt een mogelijk verband tussen een aantal ziekten, waaronder ME/CVS, en retrovirussen. De uitkomsten van twee recente studies (4,5) waarbij meer dan 85% van de ME/CVS-patinten positief werd bevonden op een retrovirus gaven internationaal aanleiding tot zorg. Er wordt momenteel wereldwijd vervolgonderzoek gedaan naar dergelijke virussen bij ME/CVS. Daarbij zijn ook Nederlandse patinten betrokken.



Meer geld voor biomedisch onderzoek nodig
ME/CVS is een complexe ziekte en de symptomen variren sterk per persoon. De huidige stand van de wetenschap laat zien dat wetenschappers onderling van mening verschillen over de beste behandeling van de ziekte. Patinten doen hun uiterste best om beter te worden en het maakt hen meestal niet uit via welke methode. Ook CGT en GET zijn daarbij door veel patinten al geprobeerd, meestal zonder veel resultaat. De ME/CVS-Stichting Nederland en de Steungroep ME en Arbeidsongeschiktheid zijn van mening dat psychologisch onderzoek, zoals CGT en GET, buitenproportioneel veel aandacht krijgt in Nederland. Dit draagt bij aan zowel een eenzijdige beeldvorming over ME/CVS als een eenzijdige ontwikkeling van behandelmethoden. Een multidisciplinaire aanpak is gezien alle wetenschappelijke ontwikkelingen op het gebied van ME/CVS op zijn plaats. De organisaties dringen daarom opnieuw aan om in Nederland meer aandacht te geven aan en geld te investeren in biomedisch onderzoek. Gebeurt dat niet dan blijven ME/CVS-patinten in Nederland vooralsnog de dupe van een ontoereikend behandelaanbod, die ook de maatschappij veel geld blijft kosten.



De ME/CVS-Stichting Nederland behartigt de belangen van mensen met ME/CVS op het gebied van medisch en sociaal-maatschappelijke zorg, door het geven van voorlichting en het verzorgen van lotgenoten contact. Meer informatie www.me-cvs-stichting.nl of telefoon 035 6211290



De Steungroep ME en Arbeidsongeschiktheid behartigt de belangen van ME/CVS-patinten op het gebied van werk, inkomen, school/studie en voorzieningen. Meer informatie: www.steungroep.nl of telefoon 050 549 29 06.





Noten:

1.patientensurveys:
http://sacfs.asn.au/news/2009/09/09_20_adverse_reactions_to_get.htm

http://www.meassociation.org.uk/?p=951

http://www.afme.org.uk/news.asp?newsid=1045

2.http://freespace.virgin.net/david.axford/me-pace.htm

3.In de Lancet is adaptive pacing onderzocht. Dit is een andere vorm van pacing dan wat het overgrote deel van de patinten hier onder verstaat. In deze laatste vorm wordt niet verondersteld dat de ziekte onomkeerbaar is of dat activiteiten gepland moeten worden met behulp van een dagboek. Pacing is daarbij ook geen therapie, maar een strategie.

4.Vincent C. Lombardi, Francis W. Ruscetti, Jaydip Das Gupta, Max A. Pfost, Kathryn S. Hagen, Daniel L. Peterson, Sandra K. Ruscetti, Rachel K. Bagni, Cari Petrow-Sadowski, Bert Gold, Michael Dean, Robert H. Silverman and Judy A. Mikovits. Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Science Vol. 326 no. 5952 pp. 585-589; http://lannieinthelymelight.blogspot.com/2011/01/part-1-11711-xmrv-presentation-by-dr.html

5.Shyh-Ching Lo, Natalia Pripuzova, Bingjie Li, Anthony L. Komaroff, Guo-Chiuan Hung, Richard Wang, and Harvey J. Alter. Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors. PNAS, August 23, 2010

The second is a reply to a newspaper article. Unfortunately it wasn't published.

http://www.steungroep.nl/index.php/...ikel-nrc-bewegen-of-denken-tegen-vermoeidheid

24-2-11: Reactie ME/CVS Stichting en Steungroep op artikel NRC: Bewegen of denken tegen vermoeidheid
24 februari 2011: Gezamenlijke reactie van ME/CVS Stichting Nederland en Steungroep ME en Arbeidsongeschiktheid op het in NRC verschenen artikel van 18 feb 2011 - Bewegen of denken tegen vermoeidheid van Nienke Beintema


Gijs Bleijenberg blaast resultaten onderzoek The Lancet sterk op

Met name Britse en Nederlandse psychiaters en psychologen claimen dat ze de beste behandelingen hebben tegen ME/CVS. Deze blijken in de praktijk voor het grootste deel van patinten niet werkzaam. Onze kritiek richt zich op drie punten:

1) Voor deze Britse studie werden patinten geselecteerd op basis van te ruime criteria. Veel patinten die (ook) een psychiatrische aandoening hebben zijn meegenomen in het onderzoek. In deze studie blijkt dat bij bijna de helft van de patinten het geval.

2) Ernstig zieke en jonge ME/CVS-patinten uitgesloten bij onderzoek

Als voorwaarde werd gesteld dat patinten konden reizen naar de plaats waar de therapie werd gegeven. Ernstig zieke ME/CVS-patinten konden daardoor niet meedoen aan het onderzoek. Ook jongeren tot 18 jaar werden uitgesloten.

3) Uit het gepubliceerde Lancet onderzoek blijkt dat cognitieve gedrag therapie (CGT) en graded excercise therapy (GET) bij 59% van de patinten geen effect heeft. Bij 41% was het positieve effect slechts matig, luidt de conclusie. De resultaten van het onderzoek worden door Gijs Bleijenberg sterk overdreven.

Meer dan 4000 wetenschappelijk gepubliceerde artikelen over ME/CVS wijzen naar een bio-medische oorzaak. Bij gedegen medisch onderzoek van ME/CVS-patinten worden vele lichamelijke afwijkingen gevonden. In 2010 werd gepubliceerd dat 85% van de ME/CVS patinten een retrovirus bij zich draagt. ME/CVS is een ernstig invaliderende ziekte. Het is misleidend te suggereren dat ME/CVS verdwijnt door louter meer bewegen of anders gaan denken.

M. Koolhaas, Steungroep ME en arbeidsongeschiktheid
M. Ham, ME/CVS-Stichting Nederland

 

[Graham]

I had a think the other day about this and sketched out a few of my views on the kind of presentation we need that ends up lacking. I'm a big believer in the value of "Don't make me think" approach to presentation. Just because doctors are smart doesn't mean that messages don't get across to them easier if things are spelled out in a clear and user-friendly way. So: here are my ideas about what's needed as a final output, and a rough sketch of the sort of format I have in mind, as an example. Kep point is making it accessible at every level: headlines, super-readable summaries, links out to greater detail, and full quotes and references to back it up:

I agree entirely Mark. On the one hand there is so much that is wrong with this study (and so many many others) that it is hard to restrain ourselves, but on the other hand, we need people to listen, and so many will just switch off if it gets complex. Sadly this is just as true of the people who are responsible for our medical care.

But I disagree with your presentation in one key area. If we are to get people who are not on our side to actually take notice, we must make the facts hammer the points home, and not indulge in opinion (such as "one of the most flagrant..."). I know you are right - it was appalling, but I am sure that we are more likely to get people to read it if we let the facts pile up and prove the case for us. For that reason, I would avoid the topic of conflict of interests - it is both relevant and important, but you have to earn credit in the reader's mind before you can start to dish the dirt. It is more the sort of thing that you keep up your sleeve for questions/follow-ups afterwards.

Unfortunately, people critical of these trials have already been painted as angry reactionaries (or some such thing), so I think that if we come out with all guns blazing, we will be ignored. Perhaps we ought to adopt the hunting style of the Komodo dragon - it just aims at getting a quick bite in, then leaves the wound to fester away, until finally the target dies.

Apart from the "emotive" words in it, I think your protocol example is what we should aim for - choose one specific area concern, and hit it with a clear-cut example carefully chosen for simplicity. Then make sure that somewhere it is made clear that we have only picked one example in each category (again, saving others for follow-up).

The only question is (as far as I am concerned) - is it better to get the 10 point summary ready and out to roll as quickly as possible, and leave the deeper stuff for later?

Sorry if this is a bit pushy for a newbie.

 

[Mark]

But I disagree with your presentation in one key area. If we are to get people who are not on our side to actually take notice, we must make the facts hammer the points home, and not indulge in opinion (such as "one of the most flagrant..."). I know you are right - it was appalling, but I am sure that we are more likely to get people to read it if we let the facts pile up and prove the case for us.

I agree with that - that's why I tried to focus on the structure and length of the format I had in mind and the general gist. You're quite right that I tend to come from an over-emotional direction at times with such things, so my words weren't important, it was the simplicity of the structure I'm trying to point at.

That said, this does depend on the audience somewhat. More opinionated expressions may have their place as well - perhaps when aiming at the general public rather than at scientists and doctors we are allowed to at least say "why we are angry", just as we do here on PR. But even there "one of the most flagrant" probably has no place.

For that reason, I would avoid the topic of conflict of interests - it is both relevant and important, but you have to earn credit in the reader's mind before you can start to dish the dirt. It is more the sort of thing that you keep up your sleeve for questions/follow-ups afterwards.

I'm not sure I agree with that, though, but I suppose it depends on what you mean by "afterwards" because I am thinking about a full (but tersely structured) explanation of what is wrong with the study and that's a crucial point. In this case I believe it's been shown that all, or nearly all, of the authors are linked to the insurance industry and listing those links - as I think Professor Hooper did - seems entirely legitimate to me.

Unfortunately, people critical of these trials have already been painted as angry reactionaries (or some such thing), so I think that if we come out with all guns blazing, we will be ignored. Perhaps we ought to adopt the hunting style of the Komodo dragon - it just aims at getting a quick bite in, then leaves the wound to fester away, until finally the target dies.

Interesting analogy!

Apart from the "emotive" words in it, I think your protocol example is what we should aim for - choose one specific area concern, and hit it with a clear-cut example carefully chosen for simplicity. Then make sure that somewhere it is made clear that we have only picked one example in each category (again, saving others for follow-up).

I think really the core point I was driving at is the structure - there are plenty of people who are great at addressing all the other issues you've raised but I want to contribute the idea of making it practical to drill down to whatever level of detail the reader desires.

The obvious way to do this is through web links - one can present the list of summary headlines and their explanations in the format I have done, and then a link from each one to the greater levels of detail and references. That would be good, on some web site, but I'll just highlight that an even better paradigm is the use of "show/hide" links, where you click a link to show the extra level of detail on an issue. For multilevel content such as this, that would be a huge step forward in presentation. Facilities for this kind of work will be coming to a website near you soon...

The only question is (as far as I am concerned): is it better to get the 10 point summary ready and out to roll as quickly as possible, and leave the deeper stuff for later?

Yes, I think you're absolutely right, start with the summary and work your way down: spot on. First job is the list of "headlines"...then a couple of sentences on each.

Really you need a good wiki (better than ours) for this, otherwise you need somebody to take a lead on the work. But again...coming soon...

Sorry if this is a bit pushy for a newbie.

Not in the least! Push away!

 

[Graham]

OK Mark, here comes the pushy newbie.

I generally find it is easier to work with something and knock it into shape, so here are my ideas. I'm not the sensitive sort, so I really won't mind how much of it you feel is rubbish: all that concerns me is that we end up with something useful and good.

My thinking went along the lines of how I used to mark statistics coursework. First determining the measurement systems, and setting up the targets for assessing success or failure. In a decent scientific study, these should be trialled and then the decisions more or less set in stone. (From what I can see, items 2. 3 and 4 were changed during the study.) Then the sampling, splitting into groups, and setting up a control group. Then the acquisition and processing of the data, followed by the actual results (and whether the results were successful or not according to the preset criteria). In addition, I have added another item - things that come to light after the trial.

1. They abandoned objective measures.
2. They used a fatigue scale where the average score was 28/33, so the only real way was up (Bill's random walk).
3. They redefined Normal
4. They set a very low target of an improvement in the average score of 2/33 in fatigue and 8/100 in SF36.
5. The use of the Oxford Criteria mean that there were many subgroups. A therapy that helped one subgroup, but did nothing for the others, even harming a few, would nevertheless show an improvement.
6. Many were excluded from the sample (your no.1)
7. They did not set up a control group, although they almost treated the SMC group as though it was one. Members of that group didn't receive the same attention of course, and if results are weak, a proper control group is essential to evaluate the placebo effect.
8. They trivialise adverse events.
9. The actual results were very poor: if you subtract the improvement made by the SMC group from the GET+SMC or CBT+SMC results, SMC in general outperforms GET or CBT. That could mean a large placebo effect: it could mean that having specialist medical attention prescribe drugs to help with pain/sleep is significant.
10. Subsequently we are told that it takes 7 or 8 patients to follow the therapy for a year for one to show a clinically significant improvement (not a return to near normality). That means that 6 or 7 have wasted their time. Sorry, that's a bit emotive ;-)

I think the order should be different though: it should be in an order that gives the most impact. I think perhaps 8, 9 and 10 create the initial impact, then the others home in on the reality of why it was such a bad study.

Over to you!