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Tuller and Rehmeyer Trial By Error, Continued: Did PACE Really Prove that GET is safe

anciendaze

Senior Member
Messages
1,841
Our anonymous debating opponent on disqus seems to have concluded the discussion without learning anything. We can tell he/she is an American somehow connected with virology blog, but that is all. He/she doesn't seem to think PACE has had a significant effect on official policy. Anyone in the U.K. want to respond?

He/she seems to think the issue of objective measurements is irrelevant to the study, and that I am proposing something new by suggesting measuring total patient activity levels before during and after treatment. This was in the original proposal. This particular series of measurements was dropped, but the claim that the study showed objective improvement in CFS patients has never been retracted, nor has a definition of "recovery" which leaves "recovered CFS patients" performing like patients with stage III congestive heart failure. Treatment which moved such heart patients from stage III to stage II would be considered clinically significant, the reported changes would not -- even in a disease which is known to be difficult to treat. So why is this considered clinically significant for CFS?

My comment about the problem of using subjective responses to rule out harms doesn't seem to have survived. If you have no idea if there was an increase or decrease in total activity how on Earth do you objectively decide if patients advanced or declined?

I am sorry for the digression on ME or ME/CFS simply because it was possible to fault the study on the basis of the CFS they claimed to be studying. Despite the statement that the authors have clearly distinguished Oxford definition CFS from ME I could point to repeated statements to the contrary. They don't even think ME exists. Obfuscation is characteristic of this bunch.

It is hard to tell that the Oxford criteria or the London definition in use in PACE defines any single clinical entity. The informally reported distinction between responders and non-responders strongly suggests that detailed data would show they did not have a homogeneous cohort, despite exercising enormous selectivity to reduce an intake of 3158 patients diagnosed by published criteria to those 640.

Beyond the dubious increase in distance walked in 6 minutes, based on incomplete data, what other objective measures of patient benefits did PACE provide?

Did the "step test" show a change in physical performance? Not at all.
Did "recovery" mean a return to employment? No.
Was there a reduction in need for sickness benefits? No, there was a small increase.
Were the alleged benefits sustained, as assumed in the economic analysis? Not at all.

At 3 years it is nearly impossible to distinguish patients in different arms of the study,
though both specialist medical care (the "control") and adaptive pacing look like reasonable long-term alternatives. Nothing objective supports the hype about CBT/GET.

So why do the authors get away with repeatedly claiming objective evidence in favor of these?
 
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13,774
There are a couple of patients who go on about ME and CFS being totally different and seem to think that all the PACE work is a distraction from their campaign: to be honest, I just think that they don't understand the issues. If you're debating with one of them, and finding that you're not getting anywhere, it might not be your fault.
 

Countrygirl

Senior Member
Messages
5,429
Location
UK
Our anonymous debating opponent on


They don't even think ME exists. Obfuscation is characteristic of this bunch.

They do according to this lecture by White in 2008. He comments on Ramsey ME and says that this is not CFS. He doesn't believe that ME patients were involved in PACE, although he makes it clear that he belives the condition was real. Listen at 24mins for his view.


 

halcyon

Senior Member
Messages
2,482
He doesn't believe that ME patients were involved in PACE
The 2011 PACE paper states otherwise:

Findings
We recruited 641 eligible patients, of whom 160 were assigned to the APT group, 161 to the CBT group, 160 to the GET group, and 160 to the SMC-alone group. Compared with SMC alone, mean fatigue scores at 52 weeks were 3·4 (95% CI 1·8 to 5·0) points lower for CBT (p=0·0001) and 3·2 (1·7 to 4·8) points lower for GET (p=0·0003), but did not differ for APT (0·7 [−0·9 to 2·3] points lower; p=0·38). Compared with SMC alone, mean physical function scores were 7·1 (2·0 to 12·1) points higher for CBT (p=0·0068) and 9·4 (4·4 to 14·4) points higher for GET (p=0·0005), but did not differ for APT (3·4 [−1·6 to 8·4] points lower; p=0·18). Compared with APT, CBT and GET were associated with less fatigue (CBT p=0·0027; GET p=0·0059) and better physical function (CBT p=0·0002; GET p<0·0001). Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results. Serious adverse reactions were recorded in two (1%) of 159 participants in the APT group, three (2%) of 161 in the CBT group, two (1%) of 160 in the GET group, and two (1%) of 160 in the SMC-alone group.

And also this statement, which I think is one of the most egregious in the entire paper.
The PACE findings can be generalised to patients who also meet alternative diagnostic criteria for chronic fatigue syndrome12and myalgic encephalomyelitis13 but only if fatigue is their main symptom.

It takes a lot of arrogance to claim that your findings apply to patients using criteria that you never even tested.
 

Countrygirl

Senior Member
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5,429
Location
UK
Isn't there some evidence that White stated that ME patients were excluded from the trial ------------------or did I dream it? (It hasn't been mentioned recently.) I cannot recall where I read it. Sorry!

Also, Dr William Weir reported that White said to him after a radio interview where he projected the idea that he did accept ME and CFS as physical conditions that in reality he didn't and that the patients just have faulty illness beliefs. I read this during in the last few days and can't recall where. :oops: It might be a useful piece of evidence.

He certainly is a slippery and duplicitous character!
 

anciendaze

Senior Member
Messages
1,841
...It takes a lot of arrogance to claim that your findings apply to patients using criteria that you never even tested.
This is what I mean by obfuscation. They have made statements which certainly appear to contradict other claims by the same people. A reasonable deduction from this would be that those statements don't mean anything.

The claim that they have presented objective evidence of both efficacy and safety is in a different category. I suppose you can argue that questionnaires become objective evidence because the marks on paper exist independent of the people who made them, but I think that would undermine any pretensions of scientific reasoning. We keep coming back to the question of the objective basis, particularly for the claim of safety. There is absolutely no doubt that the claim has been made.

In the case of efficacy, the objective evidence boils down to a single modest shift in a group mean for GET on the 6-minute-walk test, which is contradicted by the step test. The authors themselves have argued that the 6-minute-walk test was improperly implemented, which reduces confidence in this number. A group mean is no indication of safety, half the group could have declined in performance.

What I think they are claiming is that whatever unstated declines patients exhibited were not significant harms. Coupled with very ambiguous reported results concerning hospitalization we have to seriously question what the authors would consider evidence of harm. Merely making sick people sicker does not seem to fall in that category, which tells you a lot about the study.
 

Sasha

Fine, thank you
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17,863
Location
UK
It takes a lot of arrogance to claim that your findings apply to patients using criteria that you never even tested.

51% of patients also fulfilled the London ME criteria at baseline, according to the 2011 paper, hence the claim.
 
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15,786
There are a couple of patients who go on about ME and CFS being totally different and seem to think that all the PACE work is a distraction from their campaign: to be honest, I just think that they don't understand the issues. If you're debating with one of them, and finding that you're not getting anywhere, it might not be your fault.
Aside from desperately clinging to an ineffective argument, they tend to do a piss-poor job of getting their point across. Most of the anonymous comments from one person seemed to be saying that ME and/or CFS isn't a disease, or isn't a biological disease. That isn't what they meant, yet that is the impression they are giving even to people well acquainted with the ME v CFS issue, and obviously to the general public as well.

I wish they could find a way to engage in advocacy which isn't so senselessly combative, divisive, and confusing.
 

A.B.

Senior Member
Messages
3,780
I wish they could find a way to engage in advocacy which isn't so senselessly combative, divisive, and confusing.

Or it's a psychobabbler posing as patient. Engage conspiracy mode :ninja::nervous:. I couldn't help but think of that since he or she is attacking patients, Tuller and Rehmeyer while overlooking or downplaying PACE trial flaws, and pretending that White et. al. aren't treating ME and CFS as the same thing. Yes White is on record saying that Ramsay ME is a different disease... but he also thinks that ME/CFS patients don't have Ramsay ME but a psychosocial disorder.
 

Sidereal

Senior Member
Messages
4,856
I don't think it matters what White said about Ramsay ME in some obscure video. For all intents and purposes (medical system, welfare etc.) ME = CFS in the world we live in. Making purist arguments, sticking head in the sand and pretending like PACE doesn't apply/matter to ME patients in the real world, and attacking patients instead of focusing on the real enemy is a really deranged approach to advocacy.

White seemed to be implying that what is called ME today is CFS, not the Royal Free Disease aka Ramsay ME. I don't think he would diagnose any of us with Ramsay ME.
 

anciendaze

Senior Member
Messages
1,841
There is a great deal of innuendo loose in this field. Expanding or contracting definitions to serve the purpose of the moment is a standard tactic for suggesting more significance than you can show. However, there is a very serious consequence of variable definitions which is directly relevant to the question of safety or harms.

The vast majority (80%) of 3158 patients referred to the authors as "CFS" patients by NHS doctors, based on previously published material dominated by these same authors, were not in this study. Based on informal statements by these authors we learn that 60% of test subjects were "responders", leaving 40% "nonresponders". This imprecise estimate already suggests that 256 patients in the study would not benefit, which implies that at least 1,200 of the initial intake were not good candidates for this therapy. This is not a negligible fraction.

It is quite possible this shows that despite a great deal of selection, the authors did not have a homogeneous cohort. They still have no way to predict response in advance.

Now I'm going to go back in medical/psychiatric history to consider harms in a well-studied example. There were always potential problems with antidepressants in some patients. If doctors were lucky this would be like blood pressure changes in patients on MAO inhibitors, which could be revealed by simple measurements. Many of these problems were ignored anyway, and some patients suffered strokes or died. It took some time for many doctors to catch on. Unfortunately, we don't have the kind of quality data needed to follow this part of medical history in detail, though what we have is disturbing.

Research later produced drugs called SSRIs which did not have such dramatic physiological manifestations. These were impressive in initial applications because they could produce results in as little as a week. Wild enthusiasm over drugs that actually had positive effects on some patients led to books like "Listening to Prozac" (fluoxetine). Warnings about physiological changes were modest.

From the beginning there was never any question about all patients benefiting. In typical studies less than half experienced the dramatic improvements touted. In addition, there were always some patients who experienced a full range of side effects without getting any detectable benefit. This was true from day one, but was not emphasized.

Once the drug was approved for depression, doctors began prescribing it to patients who were clearly depressed. From a legal standpoint approval, and the studies on which approval was based, made it safe for doctors to prescribe, though not necessarily for patients to take. Failure to prescribe the "wonder drug" if a patient wanted it could be considered malpractice.

I still run into doctors who write these prescriptions who are at a loss concerning side effects. They don't even know that patients will generally feel worse before they feel better. In this clinical environment it was inevitable that some patients who experienced side effects before benefits, or never experienced benefits at all, would commit suicide, the clearest danger in clinical depression.

After a period of years, warnings were added concerning suicide among adolescents precipitated by Prozac. These were later extended to other depressed patients who did not experience benefits or know what was going on. Despite these you still have clinicians as ignorant as described above prescribing the drug in contexts where it is inappropriate.

With depressed patients mixed in with the initial intake of those who ended up in PACE, and a full year in which a patient might feel worse, rather than a week, the question of harms to non-responders and adverse responses becomes non-trivial. If the study authors themselves can't separate the sheep from the goats in advance we have to ask how anyone else is supposed to do this, and how many patients we can expect to die from suicide or preventable accidents involving "brain fog".

From an anecdotal standpoint this kind of accident shows up very often in discussing case histories. Frequently, this is the point where a patient realizes they are unable to cope with the problem alone. This is likely to be the onset of long-term disability, a non-trivial consequence both for the patient and for public health.
 

anniekim

Senior Member
Messages
779
Location
U.K
I think fhe person writing under the article insisting ME is not CFS and as such Pace is nothing to do with ME is someone who writes on Facebook forums with the same argument under so many topics. They go over the same thing again and again like a stuck record and many people just give up debating with them as they don't engage. It might not be them but i think it could be. I blocked this person on Facebook

In the UK ME amongst doctors is thought synonymous with CFS for most medical professionals in the UK (putting aside discussions on different case definitions) and if PACE is continued to be viewed as showing GET and CBT have modest benefits for some this will be applied to all patients in the UK be they diagnosed M.E, CFS/ME or CFS
 
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anciendaze

Senior Member
Messages
1,841
@anniekim

I have other private mentions of a possible identity. I'm not very interested in getting into a dispute about who this is, and prefer to confine discussion to actual issues, not people. You can't change who you are, but you can change behavior.

One question about ME vs. CFS, is it even possible for an NHS doctor to report that a patient has ME? I know this is discouraged. I suspect there are even senior people in the NHS who would change the diagnostic code, if allowed.

This is still basically off-topic. I'm working to finish a post tying the loose ends in this thread together with the stated topic: How far was PACE from demonstrating safety of GET?
 

anniekim

Senior Member
Messages
779
Location
U.K
Apologies I didn't want to engage in a dispute whom this person is. I just wanted to share for people to consider not exerting too much energy in engaging with this person as if it is who I think it may be they will not engage.

In answer to your question, i think UK doctors have occasionally given people the diagnosis M.E, and some still do, but I think more say CFS. Patients refer to ME much more. My official diagnosis in 1998 when I was mild (severe for last ten years) was CFS. A doctor at my local NHS CFS clinic referred to me as having ME/CFS. I have been too ill to see him for years but some recent letters from him refer to me as a severe CFS patient.
 
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Dolphin

Senior Member
Messages
17,567
What Peter White actually said was:

“The PACE trial paper refers to chronic fatigue syndrome (CFS) which is operationally defined; it does not purport to be studying CFS/ME”.

It is bizarre to see people who say ME is not CFS or CFS/ME to claim that suddenly CFS/ME equals ME i.e. to claim Peter White said they were not studying ME.

If one reads material from the PACE trial such as the Lancet paper, it is clear that they do consider that they studied ME
e.g.
"Subgroup analysis of 427 participants meeting international criteria for chronic fatigue syndrome and 329 participants meeting London criteria for myalgic encephalomyelitis yielded equivalent results."

My reading of the quote from Peter White is that he may have been thinking of the Canadian ME/CFS criteria.
 

Dolphin

Senior Member
Messages
17,567
Interesting:
Star Man disqus_Rv8tqVZbOP2 days ago
I must strongly disagree that "this whole PACE frenzy is relatively moot in the US".

My HMO (Kaiser Permanente) in the US cites the PACE trial abundantly. Their website has patient info sections such as "Chronic Fatigue Syndrome: Using Graded Exercise to Get More Energy" and "Chronic Fatigue Syndrome: Using Healthy Thinking".

When I struggled with my physician prescribed exercise program, I was encouraged to push myself to exercise as much as I could. I was told my increasing stumbling, orthostatic intolerance, breathing difficulties, and other central nervous system problems were imaginary. I was prescribed various stimulants to continue working and exercising.

A year ago, barely able to walk, I had to quit my job. I remain mostly housebound; dependent upon family and $200 per week of disability to survive.

In the United States, real patient harm and utter destruction of lives continues to occur because of this scandalous study.

  • davetuller 2 hours ago
    Hi, I'm interested in writing about the impact of PACE in the U.S. Can we talk about your experience with Kaiser Permanente?
 

anciendaze

Senior Member
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1,841
...My reading of the quote from Peter White is that he may have been thinking of the Canadian ME/CFS criteria.
Quite possibly. However, in strict logic I would point out this contains an unproven assumption that he was thinking.
 

anciendaze

Senior Member
Messages
1,841
We have wandered a considerable distance from the question at the start: did PACE demonstrate safety of GET as claimed?

The dispute over subjective versus objective measures is actually important here.

We are dealing with two primary kinds of subjectivity: patient self-reports and doctor/researcher assessments. A considerable effort is made in material distributed for doctors associated with the study to discourage patients from making negative self-reports. This ought to bring those patient reports into question as any kind of objective evidence. Studies on bias introduced by peers or authority figures illustrate just how badly this can distort perceptions and reports.

Doctor/researcher assessments are another problem. We have a number of mere assertions that patients either did not experience harms, or that any setbacks they might have suffered were not caused by treatment. To call these opinions much in the way of scientific evidence is ludicrous.

We are forced to rely on researcher assertions in many aspects of this research simply because data have not been released, assuming it was even collected in the first place. We do, however, have some interesting assertions to work with.

One which was not in the formal publication, as far as I recall, was the distinction between "responders" and "nonresponders". It scarcely matters whether the actual numbers were 60/40 or 65/35, or some similar split.

What this reveals, in a way outside evaluators cannot check, is that a substantial number of patients went through a year of treatment without receiving any benefit -- in the judgment of the researchers themselves.

There was an effort to remove patients who were clinically depressed from the cohort in advance, but I see no way to estimate the number of participants who might have become clinically depressed during the trial. This is important because clinical depression, especially with suicidal ideation, is a life-threatening medical problem.

Now, I have to ask, is it reasonable to expect people who experience the collapse of careers, finances and relationships as a result of illness which wrecks both mental and physical performance to spend a year undergoing ineffective treatment without becoming depressed? Are we recommending a therapy only for saints and epic heroes?

Once this pattern of long-term illness is established, with or without depression, it is all too easy for practitioners to adopt the implicit attitude that they are dealing with "inferior people". No evidence of performance or accomplishment prior to onset is likely to change this perception. This is a serious problem in treating any chronic disease, and doubly important when causes are obscure. This has a strong impact on patient self respect.

Now, back to the question of possible patient deterioration. No group mean is going to tell you that all patients studied showed improving scores unless you have some other assurance that all results after therapy were better than those before. When group means scarcely move it is more likely than not that close to half the patients moved up and half down.

So, the assurance that the treatment is safe comes down to the assertion that any deterioration experienced by some number of unidentified patients was not clinically significant. This causes me to revise the question above. The researchers are not terribly bothered by a substantial percentage of patients going a year without perceived benefits, and are even willing to assume that some sizable number undergo a decline over the period without counting this as harm. Furthermore, the researchers are not concerned about possible additional effort patients must put into participating in therapy. What happens to those who don't have this reserve of activity?

(Actually, I don't have to ask. This is where locked wards and feeding tubes appear in a number of accounts. I can point to cases in the U.K. news where the prospect of such a transfer precipitated suicide.)

If we knew what effort patients were making to participate, and how that compared to previous capacity, we might have a better idea of how serious a burden treatment imposes on patients. We simply don't know, based on PACE, though we might have if the proposed measures of activity had been used. Nor do we have a clue about the size of possible declines in performance the researchers assure us are not significant.

If you are dealing with a range of psychiatric problems (recall that the researchers tend to class this with psychiatric problems) the period of days or weeks before treatment becomes effective is especially important. I've already mentioned the week patients on Prozac may expect to suffer in the best cases, and the danger of suicide there. What we see in this study seems to me like an absence of measures at this time granularity. Not just suicide, but even pure accidents are regularly associated with cognitive or physical deterioration on this time scale. Did such deterioration take place? We don't know, and it is quite possible the researchers don't either.

We have assertions that CFS patients, as defined in PACE, don't suffer from PEM, but no measures which might show these claims were wrong. We have anecdotal reports of longer periods of relapse in similar patients, which are simply absent here.

Were there any measures which I am missing?

My point is that if you don't test in a way which could expose harms you cannot make any assurances about absence of harms. You must simply assume the light goes off when the refrigerator door is closed.

See the logical fallacy?
 

Dolphin

Senior Member
Messages
17,567
Here's the full quote from Peter White. The final sentence of the first paragraph shows to me that he does consider he was studying ME

1. Terminology and Classification (pages 4 to 6)
We did not use the ICD-10 classification of myalgic encephalomyelitis (ME) because it does not describe how to diagnose the condition using standardised criteria, so cannot be used as reliable eligibility criteria. The PACE trial paper refers to chronic fatigue syndrome (CFS) which is operationally defined; it does not purport to be studying CFS/ME but CFS defined simply as a principal complaint of fatigue that is disabling, having lasted six months, with no alternative medical explanation (Oxford criteria). We also used the best available (operationalised) alternative criteria for CFS and ME (International [Centers for Disease Control] and London criteria) and determined which participants met these.

We did not ask for ethical approval for doctors to refer anyone “whose main problem is fatigue (or a synonym)” to enter the trial; they also had to be definitely or provisionally diagnosed as having CFS before being screened for eligibility. The full substantial amendment clarifying this is available on request.
 
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