The P2P Draft Systematic Review Is Up

[Hate ME/CFS]

I really feel that it would take someone at the level of a U.S. President or Oprah or a major world-wide celebrity to get ME/CFS for the general public to understand what it is and for any amount of funding to be devoted to research. Not that I wish it on anyone, but I feel that is what it will take.

Gingergrrl,
I wouldn't want Oprah helping us to tell the truth about ME/CFS. She would do a fluff piece on our illness, and not help our progress.

 

[Gingergrrl]

@Hate ME/CFS I didn't mean so much for her to be the messenger of explaining it medically vs. fluff. What I was trying to say was that it would take a MAJOR politician or celebrity to actually be struck with ME/CFS as a patient for anything to be done about the illness. They don't care when millions of us regular people have it but if someone of that level of celebrity and wealth had it, only then might it be taken seriously. Sorry if I didn't explain it well!

 

[biophile]

The original study protocol had two objective measures: monitoring total patient activity with actimeters; the six-minute walk test. These were listed as secondary measures, which pretty well defines the attitude of the authors. Dropping the actimeters, after they had been bought, out of concern for the trouble they were causing patients, was one gambit in dispensing with objective measures entirely. Allowing patients who declined before or after walk tests to be counted as participants without contributing any objective evidence of effectiveness was the second act. This has not changed the rhetoric of the study authors. The whole thing was a classic bait-and-switch. Only the authors know if they ever intended to go through with objective measures of effectiveness.

Just worth repeating.

This post by Snow Leopard is also worth repeating:

To me, there were two fundamental errors. The first is as you say, the assumption that if it works for a few people, then it must work for all. The PACE study if done properly could have led to data (or the very least, hypotheses) determining who would benefit from such therapies and who does not, saving much time and resources of the medical system.

The second is that there were no placebo controls and no objective evidence of improvement, so the results could simply be a matter of shifting perception, rather than an actual improvement in functioning. When I challenged them in the literature, they replied along the lines of 'oh, patients don't care about blood results, they care about subjective reports of fatigue'. Of course blood tests wasn't what I was referring to when I mentioned objective results - I was referring to actigraphy, performance on neuropsychological tests etc. I once again challenged them in a published commentary, emphasising the need of objective measurements to claim reduction of disability for non-pharmacological therapies due to the absence of a valid double blinded controlled trial. I know I am just one of many who has been stressing the importance of this. Naturally, those who I'd most like to take note have simply ignored such suggestions.

CBT/GET proponents not only seem disinterested in objective outcomes, but actively avoid them or find ways to argue that they are irrelevant. When questioned on it, they give us either red herrings or straw man arguments about what patients supposedly want, meanwhile ignoring that most of the individuals wanting objective measures are patients themselves.

 

[zzz]

I do not think that the P2P people are aware of the large pitfall of the PACE trial,
1) they don't know that the end measure value was change halfway into the study to include more patients as 'recovered'
2) they don't know that the PACE trial people refuse to release their raw data for the publis to scrutinize
3) they don't know about the covert conflicts of interest that surrounds the PACE trial
4) they are assuming that PACE included only patients with CFS however due to the broad and useless Oxford definition PACE included depressed patients and patients with idiopathic 'I've got 4 kids' patients.

Except it's even worse than that.
5) they don't know that some patients were coerced into participating in the PACE trial and threatened with termination of their treatment if they didn't participate, as clearly their decision not to participate meant the didn't want to get better
6) they don't know that the PACE trial was not merely not blinded, but that the interviewers were instructed on how to coach the patients to give the "right" answers.
7) they don't know that the authors state quite clearly in the PACE paper that they were not using even the Oxford definition of ME/CFS. Instead, they were using their own "operational" definition of CFS, which was simply a definition of chronic fatigue, nothing more or less. The authors admitted in the paper that for this reason, the study did not apply to ME/CFS, yet this statement was buried in the paper, and was subsequently ignored by the authors and other proponents of their cause.

In other words, the PACE trial, by the written admission of its own authors, had no more to do with ME/CFS than any other study of chronic fatigue. (Actually, it was undoubtedly less accurate than most studies of chronic fatigue, due to the other points that Kati and I have made.)

For people writing to the P2P panel, I think that these would all be important points to include, especially the last one.

We are once more getting screwed.

Yes, we most certainly are.

 

[medfeb]

Except it's even worse than that.
5) they don't know that some patients were coerced into participating in the PACE trial and threatened with termination of their treatment if they didn't participate, as clearly their decision not to participate meant the didn't want to get better
6) they don't know that the PACE trial was not merely not blinded, but that the interviewers were instructed on how to coach the patients to give the "right" answers.
7) they don't know that the authors state quite clearly in the PACE paper that they were not using even the Oxford definition of ME/CFS. Instead, they were using their own "operational" definition of CFS, which was simply a definition of chronic fatigue, nothing more or less. The authors admitted in the paper that for this reason, the study did not apply to ME/CFS, yet this statement was buried in the paper, and was subsequently ignored by the authors and other proponents of their cause.

Thank you for this, zzz
Very helpful.

On #5 and #6 - is there any reference for those two statements that could be included?
On #7 - I've always thought that Oxford was nothing more than chronic fatigue as that is the only criteria. What am I missing?
Also, regarding that point that PACE said it does not apply to ME/CFS - I saw that it said that the findings only apply to people with a main complaint of fatigue. And yet I also thought they said that it applied to the broader ME/CFS because they assessed patients by other criteria (I'll ignore the flaws in how they did that for the moment.) Am I missing something else?

FInally as a general question, is there a particular source that compiles the PACE quality issues that advocates have identified? There's lots of great work that has already been done and it would be good to submit that.

 

[Esther12]

Except it's even worse than that.
5) they don't know that some patients were coerced into participating in the PACE trial and threatened with termination of their treatment if they didn't participate, as clearly their decision not to participate meant the didn't want to get better
6) they don't know that the PACE trial was not merely not blinded, but that the interviewers were instructed on how to coach the patients to give the "right" answers.

There are lots of problems with PACE, but I don't think that those are really right.

I think that there was one centre where the only provision of treatments was as part of the PACE trial, but that patients could otherwise chose not to take part and receive treatment as normal.

I've not seen anything related to 6.

 

[Esther12]

Oops, missed this post:

FInally as a general question, is there a particular source that compiles the PACE quality issues that advocates have identified? There's lots of great work that has already been done and it would be good to submit that.

There is this thread, but it's a bit out of date:

http://forums.phoenixrising.me/inde...ques-links-thread-no-discussion-please.14121/

There are Graham's videos and the associated site.

Ummm... I'm not sure if I can think of anything recent.

 

[Dolphin]

7) they don't know that the authors state quite clearly in the PACE paper that they were not using even the Oxford definition of ME/CFS. Instead, they were using their own "operational" definition of CFS, which was simply a definition of chronic fatigue, nothing more or less. The authors admitted in the paper that for this reason, the study did not apply to ME/CFS, yet this statement was buried in the paper, and was subsequently ignored by the authors and other proponents of their cause.

If you mean the Oxford definition of CFS (I don't know of any Oxford definition for ME/CFS), I don't recall anything like this.

 

[Esther12]

re 7) Oxford: I took that to just mean that the exact criteria used by PACE (eg SF-36 <65) are not laid out in the Oxford criteria, and were then changed as part of PACE. That's just the way it is though.

 

[Dolphin]

re 7) Oxford: I took that to just mean that the exact criteria used by PACE (eg SF-36 <65) are not laid out in the Oxford criteria, and were then changed as part of PACE. That's just the way it is though.

I think using SF-36 <=65 to operationalise the Oxford criteria is reasonable enough. And the change was minimal (SF-36<=60 to SF-36<=65). I don't think this would justify a claim that

the authors state quite clearly in the PACE paper that they were not using even the Oxford definition of ME/CFS

(if ME/CFS is read to mean CFS as there are no Oxford ME/CFS criteria).

 

[user9876]

I think using SF-36 <=65 to operationalise the Oxford criteria is reasonable enough. And the change was minimal (SF-36<=60 to SF-36<=65). I don't think this would justify a claim that
(if ME/CFS is read to mean CFS as there are no Oxford ME/CFS criteria).

I thought the change was in using the SF36 scale to operationalise the oxford criteria was for judging whether people met the diagnostic criteria after treatment rather than as part of the selection criteria.

 

[Dolphin]

I thought the change was in using the SF36 scale to operationalise the oxford criteria was for judging whether people met the diagnostic criteria after treatment rather than as part of the selection criteria.

No, entry criteria were SF-36 <=60 (changed to SF-36 <=65 part-way through recruitment) and CFQ >=6 (bimodal scoring).

 

[worldbackwards]

@Hate ME/CFS I didn't mean so much for her to be the messenger of explaining it medically vs. fluff. What I was trying to say was that it would take a MAJOR politician or celebrity to actually be struck with ME/CFS as a patient for anything to be done about the illness. They don't care when millions of us regular people have it but if someone of that level of celebrity and wealth had it, only then might it be taken seriously. Sorry if I didn't explain it well!

Former UK Secretary of State at the Department of Work and Pensions Yvette Cooper was diagnosed with ME earlier in her career, and has fully recovered (fair to say what she advocated as helping her sounded more like pacing than anything else). During her time, she didn't show a lot of kindness to anyone claiming sickness benefits and acceptance rates fell through the floor. Political priorities are rarely personal ones.

 

[zzz]

On #5 and #6 - is there any reference for those two statements that could be included?

Most certainly. Professor Malcolm Hooper's 442-page analysis of the study documents all of this. For example, Point #5 is covered in depth on pages 228 through 231, in the section entitled "Coercion to take part in the MRC PACE Trial?" Although I can't currently find the exact incident to which I was referring in #6, there are plenty of similar incidents listed in Professor Hooper's paper. For example, there is the section "Blinding / Unblinding" on pages 287 and 288. On page 57, it is stated that the PACE,Participants’ Newsletter Issue 3 (December2008) specifically contained disparaging material about Dr. John Chia's work in an obvious attempt to discredit biomedical evidence and influence the patients that way; the newsletter material is included in Professor Hooper's paper. On page 252, in the section entitled "Undue influence on the PACE Trial outcome", there is much documentation on how the patients were coerced into providing only positive feedback.

And I've even discovered something new. At the bottom of page 57, there is a section entitled, "Attempts to reclassify fibromyalgia (FM) as a mental disorder". To summarize, Wessely and others have stated that there is only one "functional somatic syndrome". This being the case, fibromyalgia patients were included in the PACE trial. As fibromyalgia patients respond better to GET than ME/CFS patients do, this would obviously have a confounding effect on the results.

As for Point #7, Professor Hooper quotes the Trial Identifier at section 3.6 from the PACE document:

“Subjects will be required to meet operationalised Oxford criteria for CFS. This means six months or more of medically unexplained, severe, disabling fatigue affecting physical and mental functions. We chose these broad criteria in
order to enhance generalisability and recruitment”.

As Professor Hooper comments,

Deliberately to broaden entry criteria for a clinical trial so that they include patients who do not have the disorder in question would seem to contravene elementary rules of scientific procedure.

Furthermore, in the article "Case definitions and diagnostic criteria for Myalgic Encephalomyelitis and Chronic fatigue Syndrome: from clinical-consensus to evidence-based case definitions" in Neuroendicrinology Letters, Vol. 34, No.13 2013, it is stated,

In a letter to the editor of the Lancet it is stated: “The PACE trial paper refers to chronic fatigue syndrome (CFS) which is operationally defined; it does not purport to be studying CFS/ME” (Hooper 2011)

Specifically, there were many letters of complaint to the Lancet after the PACE Trial was published. The authors of the PACE Trial responded, and their response was forwarded by the Lancet to Professor Hooper, who had written one of the letters of complaint. In his response, Professor Hooper quotes Peter White and the others as follows:

In their letter, Peter White et al state: “The PACE trial paper refers to chronic fatigue syndrome (CFS) which is operationally defined; it does not purport to be studying CFS/ME”. (Source: Professor Hooper, 'Initial response by Professor Malcolm Hooper to an undated letter sent by Professor Peter White to Dr Richard Horton, Editor-in-Chief of The Lancet' (mecfsforums, 18 May 2011) )

As for the Oxford definition itself, from the Journal of the Royal Society of Medicine, Volume 84, 1991:

Diagnosis

Signs
There are no clinical signs characteristic of the condition, but patients should be fully examined, and the presence or absence of signs reported.

Syndromes

Two broad syndromes can be defined:

Chronic fatigue syndrome (CFS)

(a) A syndrome characterized by fatigue as the principal symptom.
(b) A syndrome of definite onset that is not lifelong.
(c) The fatigue is severe, disabling, and affects physical and mental functioning.
(d) The symptom of fatigue should have been present for a minimum of 6 months during which it was present for more than 50% of the time.
(e) Other symptoms may be present, particularly myalgia, mood and sleep disturbance.
(f) Certain patients should be excluded from the definition. They include:

(i) Patients with established medical conditions known to produce chronic fatigue (eg severe anaemia). Such patients should be excluded whether the medical condition is diagnosed at presentation or only subsequently. All patients should have a history and physical examination performed by a competent physician.
(i) Patients with a current diagnosis of schizophrenia, manic depressive illness, substance abuse, eating disorder or proven organic brain disease. Other psychiatric disorders (including depressive illness, anxiety disorders, and hyper- ventilation syndrome) are not necessarily reasons for exclusion.​

Post-infectious fatigue syndrome (PIFS)

This is a subtype of CFS which either follows an infection or is associated with a current infection (although whether such associated infection is of aetiological significance is a topic for research). To meet research criteria for PIFS patients must
(i) fulfil criteria for CFS as defined above, and
(ii) should also fulfil the following additional criteria:

(a) There is definite evidence of infection at onset or presentation (a patient's self-report is unlikely to be sufficiently reliable).
(b) The syndrome is present for a minimum of 6 months after onset of infection.
(c) The infection has been corroborated by laboratory evidence.​

So the Oxford definition differs slightly from just chronic fatigue, but not by very much. However, it does not automatically include people with fibromyalgia, as the PACE trial did.

FInally as a general question, is there a particular source that compiles the PACE quality issues that advocates have identified? There's lots of great work that has already been done and it would be good to submit that.

Yes; Professor Hooper's 442 page manuscript is considered the definitive critical work. I came across many other surprising things in there just preparing this. It's a fascinating read, if you can stomach it.

There are lots of problems with PACE, but I don't think that those are really right.

Unless you've read Professor Hooper's entire document, you're bound to be in for a number of surprises.

If you mean the Oxford definition of CFS (I don't know of any Oxford definition for ME/CFS), I don't recall anything like this.

Yes, I do mean CFS. Not being from the UK, the fact that multiple terms (CFS, CFS/ME, ME) can be used in the same country to mean either the same or different things depending on who's using them can be a bit confusing at times. I think I've got it now, though...

 

[Bob]

7) they don't know that the authors state quite clearly in the PACE paper that they were not using even the Oxford definition of ME/CFS. Instead, they were using their own "operational" definition of CFS, which was simply a definition of chronic fatigue, nothing more or less. The authors admitted in the paper that for this reason, the study did not apply to ME/CFS, yet this statement was buried in the paper, and was subsequently ignored by the authors and other proponents of their cause.

The Oxford CFS criteria select patients with chronic fatigue: Diagnosis using the Oxford criteria requires six months of chronic fatigue, and no other symptoms are required.

The Oxford criteria were operationalised for the PACE trial, but that's normal practise for a research study, and I think it made little difference in terms of what sort of patients were recruited.

In correspondence, subsequent to publication, the authors of the study have said that the PACE trial studied 'CFS', and not 'ME', but the correspondence wasn't published in a peer-reviewed journal (as far as I recall) so it can't be used as evidence. It was just a comment in a letter. (But the Oxford CFS criteria diagnoses chronic fatigue patients anyway, so the letter is not needed for evidence.)

After patients were selected for the PACE trial, using the Oxford CFS criteria, the participants were subsequently subgrouped using Reeves (2003) and the London ME criteria. I think this can be considered bad practice, and not a true representation of a Reeves cohort or a London ME cohort, because patients were already selected (and filtered) using a different criteria by the time the sub-grouping took place. There were no major differences between the subgroups at the end of the trial.

5) they don't know that some patients were coerced into participating in the PACE trial and threatened with termination of their treatment if they didn't participate, as clearly their decision not to participate meant the didn't want to get better

I've not come across this before.

6) they don't know that the PACE trial was not merely not blinded, but that the interviewers were instructed on how to coach the patients to give the "right" answers.

Patients were not blinded to treatment (as it's not possible to in a trial like this.)
Also, no placebo control was used.
So the quality of the trial could be considered poor.

 

[Bob]

Re the PACE trial, neither employment, welfare benefits or private insurance claims improved after treatment with CBT/GET. (These were the three objective measures used in addition to the six minute walking distance test.)

Also, for objectively measured physical disability (using the six minute walking distance test), CBT failed to improve average physical disability, and GET failed to improve average physical disability by a clinically useful amount.

 

[Dolphin]

So the Oxford definition differs slightly from just chronic fatigue, but not by very much. However, it does not automatically include people with fibromyalgia, as the PACE trial did.

I'm not sure what you mean by "automatically include people with fibromyalgia". We certainly don't know that everyone in the trial has fibromyalgia. None of the CFS definitions exclude patients who have co-morbid fibromyalgia to the best of my knowledge.

 

[Dolphin]

Yes; Professor Hooper's 442 page manuscript is considered the definitive critical work. I came across many other surprising things in there just preparing this. It's a fascinating read, if you can stomach it.

It was written before any data was released (and subsequent discussions) so would give people an incomplete set of information to criticise the trial e.g. outcome measures in the protocol were changed, differences between subjective and objective outcomes, etc.

 

[Dolphin]

As for Point #7, Professor Hooper quotes the Trial Identifier at section 3.6 from the PACE document:

“Subjects will be required to meet operationalised Oxford criteria for CFS. This means six months or more of medically unexplained, severe, disabling fatigue affecting physical and mental functions. We chose these broad criteria in
order to enhance generalisability and recruitment”.

As Professor Hooper comments,

Deliberately to broaden entry criteria for a clinical trial so that they include patients who do not have the disorder in question would seem to contravene elementary rules of scientific procedure.

I don't think this should be interpreted the way you have i.e.

the authors state quite clearly in the PACE paper that they were not using even the Oxford definition of [CFS]

The "broad criteria" bit refers to the choice of using the Oxford criteria as the basis rather than another criteria such as the Fukuda criteria which are less broad.

 

[zzz]

I'm not sure what you mean by "automatically include people with fibromyalgia".

In other words, people with fibromyalgia were included whether or not they met the fatigue criteria.

We certainly don't know that everyone in the trial has fibromyalgia.

No, we don't; that was never stated. I see no reason to believe that they all did.

None of the CFS definitions exclude patients who have co-morbid fibromyalgia to the best of my knowledge.

You are correct; they don't. My point, and Professor Hooper's, was simply that people with fibromyalgia could be admitted to the study without meeting the necesssary fatigue criteria associated with the Oxford definition.

Yes; Professor Hooper's 442 page manuscript is considered the definitive critical work. I came across many other surprising things in there just preparing this. It's a fascinating read, if you can stomach it.

It was written before any data was released (and subsequent discussions) so would give people an incomplete set of information to criticise the trial e.g. outcome measures in the protocol were changed, differences between subjective and objective outcomes, etc.

That's true. In that case, I don't know of a single document that encompasses everything. However, I believe that Professor Hooper's document is a severe and detailed indictment of the trial itself, and I know of no other document that is as detailed in that respect.