Thursday 15 May 2014

Excerpt from my book 'Authors of our own Misfortune?' specifically related to the PACE trial.

Below is an excerpt from my book Authors of our own Misfortune? The Problems with Psychogenic Explanations for Physical Illnesses, details of which are available on Amazon and other places:

http://www.amazon.co.uk/Authors-our-own-misfortune-explanations/dp/1479253952

This excerpt relates specifically to the PACE trial and includes the relevant footnotes. It has been formatted in order to make it 'blog' friendly here:


"A study that is exemplary of how flawed CBT and GET trials can be is the PACE trial (White et al, 2011). The results of this study were published with a massive media campaign that saw newspaper headlines such as:

Got ME? Fatigued patients who go out and exercise have best hope of recovery, finds study. (7)

An editorial in the Lancet accompanying the article claimed:

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 shown… This 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. (Bleijenberg and Knoop, 2011)

The paper 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.

But did the PACE trial adequately assess effectiveness and safety of CBT/GET, and did this study disprove patient (and medic and scientist) concerns re safety? The evidence below shows that it did not.

The trial itself was mostly funded by the Medical Research Council but also, possibly uniquely, partially funded by the UK Department of Work and Pensions. The trial cost several million pounds. It was subject to a large amount of concern and objection, from advocates for ME sufferers, from the beginning of the study in 2004. This author was one of those who outlined specific concerns at the beginning of the trial, and various concerns were also outlined in responses to the publication of the protocol mid-trial (White et al, 2007). (8)

It has already been discussed in chapter 4 how 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 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 selection 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 is a similarity of symptoms 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.(9) Therefore, to have included patients with neurological symptoms and/or signs would have meant there was a risk of other neurological conditions being involved in the trial, which would have been a major flaw rendering the trial’s findings unsafe. It is therefore likely that patients with signs and symptoms of neurological (and indeed other organic) dysfunction were 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 the very patients they claim such treatments are safe and efficacious, those given an ME or CFS diagnosis who suffer physiological impairments including neurological deficits.

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)(10) to include people with symptoms (and possibly signs) of neurological dysfunction, although they used their own (customised) 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. (11) Indeed, as is evident from the PACE Trial protocol, the 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 (in order to exclude organic disease), either at the clinic or by their GP. A study by Newton et al (2010) found that 40% of patients referred to a CFS 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, the amount of patients referred to British CFS units (or, often, ‘chronic fatigue units’), meeting the Oxford criteria for CFS and having no exclusionary conditions or organic dysfunction, would appear to be very small indeed.

This phenomenon supports the premise that, as discussed in chapter 2, general practitioners tend to adopt psychogenic explanations for somatic illnesses of uncertain aetiology (after very limited investigation), and refer patients to such units, where they are offered CBT/GET using a ’reattribution’ model, informed by psychogenic explanations for their illnesses, and given little to no further investigation, or biomedical treatment, even though such clinical patients exhibit signs and symptoms of organic dysfunction. Significantly, various primary psychiatric conditions were inclusive for admission to the PACE trial, including but not limited to Major Depressive Disorder, lifetime psychosis, and post-traumatic stress disorder (see the PACE protocol included in White et al, 2007).

Another major problem in the PACE trial was 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. (12) The PACE trial’s ‘Adaptive Pacing Therapy’ was not autonomous, being therapist led, and imposed a regime upon the patient similar to the GET treatment. Even ‘Specialist Medical Care’, as defined by PACE, was subject to instability as an approach (in that the trial doctors could and did, for example, prescribe anti-depressants ad hoc), was given to all participants of the trial, and did not function as a placebo.

Like CBT/GET trials before, even with the inherent methodological problems engendering serious risks of inappropriate bias in claims of positive outcome, the ‘positive’ outcomes of the PACE trial themselves were weak. In particular, as discussed by Kindlon:

The only objective outcome measure was the six-minute walk test, which only increased for CBT participants by 21m to 354m, a change that was actually slightly smaller than that of the control group. The GET group increased by a bit more, to 379m after 12 months… However, this still is a very low absolute walking distance for a group with a mean age of 40. By comparison, a group of older adults (mean age: 65) covered an average distance of 631m… In addition, data was unavailable for 31 per cent of GET participants and 24 per cent of those who undertook CBT; it may be the case that sicker patients were less likely to try the test. (13)

Another issue arises regarding designated ‘serious’ adverse outcomes, which, after what appears to be an ad hoc analysis, were dismissed as not ‘thought to be’ related to treatment in the Lancet article. But the accompanying Web Appendix, published online by the Lancet, indicates that some serious adverse events were acknowledged as “possibly related” to treatments in one table (Web Appendix Table C), while Table D exhibited conditions which, to those familiar with the biomedical research around ME or CFS, for example, could well have been adverse results of treatment, including blackouts, drop attacks, cardiac problems, abdominal pain, and increase in disability/incapacity. In light of the apparent stringent attempts to exclude patients with organic dysfunction in this trial, the serious adverse events evidence points to two possibilities other than the ‘not related to treatment‘ blithely claimed in the Lancet article: some patients with organic dysfunction were, by accident rather than design, included in the trial, and adverse events associated with the illness and the risks of exertion occurred; or, if the cohort did consist only of patients without organic dysfunction, increased incapacity nevertheless occurred in some patients, and this may mean even patients without organic illness do not benefit much from CBT or GET (or indeed the other treatments).

In the circumstances and bearing the above, 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 lack of understanding 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 of those patients.

FOOTNOTES

9. For example, similarities in presentation between ME or CFS and MS are discussed in Poser, 2000.

10. See online responses to White et al, 2007 .

11. See my online responses to White et al, 2007.

12. See the APS Scotland ‘Scottish Good practice Guide on ME-CFS (patient guidance)’, 2010, available at: show.scot.nhs. Accessed 20 March 2011.

13. Kindlon, 2011 op cit. The ‘older adults’ comment refers to another study unrelated to ME or CFS treatment trials. The ‘control’ group, in the context of the PACE trial, appears to refer to those receiving ‘Specialist Medical Care’ (SMC) alone (all other participants received ‘SMC‘ in addition to APT, CBT, or GET)."

Email correspondence with Charles Warlow, Lancet Ombudsman, regarding complaint about the PACE trial

The following is email correspondence I had with Dr Charles Warlow, regarding my complaint about the PACE trial that had been published in the Lancet, which had not been addressed (and remains unaddressed):

http://pacedocuments.blogspot.co.uk/2011/04/complaint-to-editor-of-lancet-regarding.html

PLEASE NOTE: This email correspondence proceeds in reverse chronological order.

----- Original Message -----
From: "ANGELA KENNEDY"
To: "Charles Warlow"
Sent: Tuesday, October 04, 2011 5:09 PM
Subject: Re: Your failure to respond to my complaint about the Lancet publication of the PACE trial

Dear Professor Warlow,

Thank you for the information. However, please note I did not request you to
recuse yourself from this investigation.

Also- you surely do understand that being a co-author of one of the authors
of a trial that is being complained about is a key Conflict of Interest?

Sincerely
Angela Kennedy


----- Original Message -----
From: "Charles Warlow"
To: "ANGELA KENNEDY"
Cc: Richard Turner
Sent: Tuesday, October 04, 2011 4:51 PM
Subject: Re: Your failure to respond to my complaint about the Lancet
publication of the PACE trial


Richard Turner is the Lancet Editor who deals with communications to
the Ombudsman, his email is............ which should
have been on the emails I sent to you and copied to him, including
this one. The Ombudsman role is to investgate complaints not about
editorial policy but about process in the dealings the Lancet has with
authors and others such as yourself. I am not taking your comments
personally, but clearly you think I am in some sort of opposing camp
to yourself and under the circumstances the Lancet will have to find
someone else to deal with your complaint. So yes, I am formally
excusing myself from this investigation, at your request. Charles


Quoting ANGELA KENNEDY on Tue, 4 Oct
2011 16:32:01 +0100:

Dear Professor Warlow,

With the greatest of respect, your lack of reimbursement for your
professional duties cannot be my concern. My concern is to have my
complaint, and the concerns that generated that complaint,
investigated promptly, fairly and accurately, with correct procedure
and transparency. So far, this does not appear to have happened.
This is very worrying.

I do not know who Richard Turner is. Would you please enlighten me?
Would you please also give me his email details, so I may write to
him? Would you also provide me with the relevant information about
the duties of a Lancet Ombudsman, and how these have been agreed and
formalised? I presume these will have been explained to you when you
took up this post?

I am hoping that you are not taking my concerns about your Conflict
of Interest personally. This is a well-known professional issue. I
myself am an academic, and am fully aware of the need for
consideration of Conflicts of Interest for ethical and scientific
probity. Indeed I have to abide by such considerations myself. I am
concerned that you do not appear to understand your own Conflicts of
Interest in this case, and seek reassurance that you do. I reproduce
here my comments from my original complaint to you:

You are a co-author with at least one of the co-authors of the PACE
trial (Michael Sharpe) that I am aware of, for example, from your
profile page at the CCBS:
http://www.dcn.ed.ac.uk/pages/profiles/profiles.asp?ProfileId=10

Systematic review of misdiagnosis of conversion symptoms and
hysteria. Stone J, Smyth R, Carson A, Lewis S, Prescott R, Warlow C,
Sharpe M. BMJ (2005) 331:

You also appear to support psychogenic explanations for illnesses of
uncertain aetiology, and therefore your views are likely to be in
harmony with the known and published views of key PACE trial authors
and assistants about illnesses such as ME or CFS, for example, your
above profile states:

"I have also had passing interests in motor neuron disease, multiple
sclerosis and nowadays in the large number of patients whose
neurological symptoms are not explained by any disease (sometimes
called somatisation or functional)."

I take it, from your comments here, that you will therefore be
formally excusing yourself from this investigation because of your
Conflicts of Interest, and informing the Lancet accordingly, and
will look forward to receiving that formal communication.

Best wishes
Angela Kennedy


----- Original Message ----- From: "Charles Warlow"
To: "ANGELA KENNEDY"
Cc: Richard Turner
sent: Tuesday, October 04, 2011 4:02 PM
Subject: Re: Your failure to respond to my complaint about the
Lancet publication of the PACE trial

Not yet, but if you have any doubts about any conflict of interest on
my part then there is absolutely no point in me taking this any
further forwar. I will copy this to Richard Turner at the Lancet
because they will have to find an alternative person - I supsect this
may not have happened before, it certainly has not in my time, so you
will I fear have to be patient until the Lancet sort this out. It is
in everyone's interests, not least the patients, that whoever looks at
your complaint is acceptable to all parties. Clearly you feel, for
whatever reason, that I am not so I will have to drop out now. I am
sure you understand that I do not want to work on your complaint for
several hours if not days and then have my judgement dismissed for
being conflicted. Charles


Quoting ANGELA KENNEDY on Tue, 4 Oct
2011 15:55:27 +0100:

Dear Professor Warlow,

Have you read my initial complaint? It is clear you have a conflict
of interest. How, in the interests of transparency, good science,
and ethics, are you going to address that conflict of interest, in
order that I may be confident that my complaint will be investigated
with the requisite fairness and objectivity?

Surely as an Ombudsman you must be aware that these issues sometimes
crop up? What is normal procedure in cases like this?

Best wishes
Angela Kennedy

----- Original Message ----- From: "Charles Warlow"
To: "ANGELA KENNEDY"
Cc: Richard Turner
Sent: Tuesday, October 04, 2011 3:38 PM
Subject: Re: Your failure to respond to my complaint about the
Lancet publication of the PACE trial

But what about your view that I have a conflict of interest? I don't
want to do a whole lot of work on this (unpaid by the way) to have you
reject my views as being biased. I need to know very clearly that you
will accept my judgement as being unconflicted, or failing that the
Lancet will have to find someone else to look at this. Charles

Quoting ANGELA KENNEDY on Tue, 4 Oct
2011 15:16:03 +0100:

Dear Professor Warlow,

Thank you for getting back to me so promptly. I wrote to you at the
email address ombudsman@lancet.com , after being informed by Zoe
Mullan that this was the address to send my complaint to. I have
never received any indication that my emails were not delivered to
this address.

I am now going to send you over, by separate emails to your
personal address:

1. Zoe Mullan's email to me demonstrating the above.
2. My initial email to you of 9th June 2011.
3. My second email to you of 7th August 2011.

I will also be sending over other correspondence related to this
subject as appropriate.

Notwithstanding your apparent confusion about this issue, I am
presuming that you, when you read this evidence, will now understand
what an extremely serious situation this is? I have written to you
in good faith. I do now expect you, as the Lancet Ombudsman, to
attend to this issue urgently, objectively, in good faith and
without prejudice.

Many thanks
Angela Kennedy

----- Original Message ----- From: "Charles Warlow"
To: "ANGELA KENNEDY
Cc: Richard Turner
Sent: Tuesday, October 04, 2011 1:16 PM
Subject: Re: Your failure to respond to my complaint about the
Lancet publication of the PACE trial

I am sorry but I have absolutely no idea what complaint you are
talking about. Did you email me personally or via the Lancet? Either
way I have heard nothing. I think you are being a little premature
in summoning your lawyers. Also perhaps you get let me know what you
mean by my conflict of interest, again I have no idea what you are
referring to. I am copying this to Richard Turner at the Lancet, he
looks after the ombudsman's post box. Charles Warlow

Quoting ANGELA KENNEDY on Tue, 4 Oct 2011 11:58:23 +0100:

Dear Professor Warlow,

I note that you have failed to respond, in any way, to either my
initial complaint of June 9th, 2011, or my second email to you of
August 7th, 2011, about the above topic.

Your failure to respond indicates you have failed to act correctly
as an Ombudsman.

In light of this this failure, I now have no option but to seek
legal advice with a view to legal action in order to pursue my
legitimate complaint, and to make public both your failure to act
correctly, and your conflict of interest in this matter.

Yours sincerely

Angela Kennedy