Wednesday, 10 February 2016

Summary of my specific concerns about PACE with annotated bibliography

This is a summary of my specific concerns about the PACE trial and its methodology, which differs to a degree to many of the other concerns currently being aired. This does not mean I do not share those other concerns. I do. but my own concerns here are more specific to other problems in PACE methodology, and provide additional fundamental reasons why the PACE trial methodology needs a critical review with a view to possible retraction. I actually believe all published PACE papers should be retracted because their 'findings' are unsafe: a consequence of the many methodological flaws of the trial. By 'unsafe' I mean both scientifically unsound and, actually more importantly, dangerous to patients.

It must be said that some of these concerns listed here have been present since at least 2004, and remain, borne out by newer evidence as it became available when the PACE trial paper was published. Others are newer concerns that arose as the paper was published and other flaws became evident.

The methodological and ethical problems I have identified are as follows:


1. Serious risks to clinical patient safety caused by unsound claims made about the efficacy of CBT and GET following the PACE trial;

2. Gross discrepancies between research and clinical cohorts, and how clinical patients (and the physiological dysfunction associated with them) appear to have been actively excluded from PACE and other research by the research group involved in PACE, which has, ironically, caused serious resulting risks to clinical patient safety in the UK in particular;

3. Related to the above, gross discrepancies in how various sets of patient criteria were used (and/or rejected), including but not limited to a changing of the London criteria by PACE authors from its original state, a set of criteria which was already controversial and problematic to start with for a number of reasons;

4. Failure of the PACE trial authors to acknowledge the range and depth of scientific literature documenting serious physiological dysfunction in patients given diagnoses of ME or CFS, and how CBT and GET approaches may endanger patients in this context;

5. The inclusion of major mental illnesses in the research cohort;

6. The distortion by PACE trial researchers of 'pacing' from an autonomous flexible management strategy for patients into a therapist led Graded Activity approach;

7. The post hoc dismissal of adverse outcomes as irrelevant to the trial, in direct contradiction to what is scientifically known about the physiological dysfunctions of people given diagnoses of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome;

8. The instability of 'specialist medical care' as a treatment category, and the lack of any sound category of 'control' group.

ANNOTATED BIBLIOGRAPHY

1. Regarding my concerns about PACE's (and other projects') studied ignoring of the Canadian Guidelines:

http://bmj.bmjjournals.com/cgi/eletters/bmj.38301.587106.63v1

Also my response "Problems in the PACE Trial" (13 November 2007)
to the White et al paper "Protocol for the PACE trial":

https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-7-6/comments

See also my complaint to the Lancet: http://pacedocuments.blogspot.co.uk/2011/04/complaint-to-editor-of-lancet-regarding.html

See also my book "Authors of our own Misfortune? The Problems with Psychogenic Explanations for Physical Illnesses" (2012) Market Rasen: The Village Digital Press, especially chapters 2, 4, and 6.

2. Regarding the problems of the London Criteria in particular:

Online exchange with Ellen Goudsmit following my response "Problems in the PACE Trial" (13 November 2007)
to the White et al paper "Protocol for the PACE trial":

https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-7-6/comments

See also an online discussion on Phoenix Rising:

http://forums.phoenixrising.me/index.php?threads/pace-trial-and-the-criteria-for-m-e-used.10766/

See also my complaint to the Lancet: http://pacedocuments.blogspot.co.uk/2011/04/complaint-to-editor-of-lancet-regarding.html


3. Regarding the problems around criteria used generally:

http://bmj.bmjjournals.com/cgi/eletters/bmj.38301.587106.63v1

https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-7-6/comments

http://forums.phoenixrising.me/index.php?threads/pace-trial-and-the-criteria-for-m-e-used.10766/

http://forums.phoenixrising.me/index.php?threads/pace-study-and-oxford-criteria.8880/

See also my complaint to the Lancet: http://pacedocuments.blogspot.co.uk/2011/04/complaint-to-editor-of-lancet-regarding.html

See also my book "Authors of our own Misfortune? The Problems with Psychogenic Explanations for Physical Illnesses" (2012) Market Rasen: The Village Digital Press, especially chapters 2, 4, and 6.

4. Regarding PACE and/or other research excluding ME patients (a neurological disease according to WHO ICD-10) with neurological dysfunction (and signs of physical illness) from research:

http://forums.phoenixrising.me/index.php?threads/pace-trial-and-the-criteria-for-m-e-used.10766/

http://forums.phoenixrising.me/index.php?threads/pace-study-and-oxford-criteria.8880/

http://forums.phoenixrising.me/index.php?threads%2Fpoll-swollen-lymph-nodes-did-you-have-these-before-getting-me-cfs-or-did-they-only-appear-after.9250%2F

See also: "RE: Authors Response" (Angela Kennedy replied to Anthony_Cleare on 13 Jan 2010 at 23:18 GMT)

http://www.plosone.org/annotation/listThread.action?root=1669

See also: Questions about 'CFS' and 'ICF' selection criteria of cohort' Response to Byrnes et al ('Expression in
Peripheral Blood Leukocytes in Monozygotic Twins Discordant for Chronic Fatigue: No Evidence of a
Biomarker' PLoS ONE 4(6): e5805 2009) 3 January 2011.
http://www.plosone.org/annotation/listThread.action?root=3801

See also: "'Cost-effectiveness' is irrelevant when safety has not even been addressed in the PACE trial 02 Aug 2012 at 11:35 GMT in response to McCrone et al "Adaptive Pacing, Cognitive Behaviour Therapy, Graded Exercise, and Specialist Medical Care for Chronic Fatigue Syndrome: A Cost-Effectiveness Analysis"

http://www.plosone.org/annotation/listThread.action?root=52481

See also my complaint to the Lancet: http://pacedocuments.blogspot.co.uk/2011/04/complaint-to-editor-of-lancet-regarding.html

See also my book "Authors of our own Misfortune? The Problems with Psychogenic Explanations for Physical Illnesses" (2012) Market Rasen: The Village Digital Press, especially chapters 2, 4, and 6.


5. Regarding claims to safety and efficacy:

http://www.plosone.org/annotation/listThread.action?root=52481

http://bmj.bmjjournals.com/cgi/eletters/bmj.38301.587106.63v1

See also my complaint to the Lancet: http://pacedocuments.blogspot.co.uk/2011/04/complaint-to-editor-of-lancet-regarding.html

See also my book "Authors of our own Misfortune? The Problems with Psychogenic Explanations for Physical Illnesses" (2012) Market Rasen: The Village Digital Press, especially chapters 2, 4, and 6.


6. Regarding the failure to address the biomedical evidence available detailing serious organic physiological dysfunction in patients who receive a 'CFS' or 'ME' diagnosis:

https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-7-6/comments

See also my complaint to the Lancet: http://pacedocuments.blogspot.co.uk/2011/04/complaint-to-editor-of-lancet-

7. Other points:

https://bmcneurol.biomedcentral.com/articles/10.1186/1471-2377-7-6/comments

See also my complaint to the Lancet: http://pacedocuments.blogspot.co.uk/2011/04/complaint-to-editor-of-lancet-

See also my book "Authors of our own Misfortune? The Problems with Psychogenic Explanations for Physical Illnesses" (2012) Market Rasen: The Village Digital Press, especially chapters 2, 4, and 6.

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


Friday, 10 June 2011

My complaint to Charles Warlow, Lancet Ombudsman, re PACE

I sent a detailed complaint yesterday, 10th June 2011, to Dr Charles Warlow, the Lancet Ombudsman. The length of the complaint precludes full publication on this blog, and the bulk of the complaint reiterates the problems in my original complaint to the Lancet of 25th April. I therefore publish here only the preamble, 3rd complaint, and concluding paragraphs.

Since I first made my complaint to Dr Horton, I have been made aware that the PACE authors have written to Professor Hooper, and that he has responded to them:
 http://www.meactionuk.org.uk/Comments-on-PDW-letter-re-PACE.htm


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

 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.
Dear Dr Warlow,

I am writing to you in your capacity as Ombudsman for the Lancet journal. I am writing to make a complaint about three issues, related to the publishing by the Lancet of the article
 and the unsafe claims made within the Lancet article and accompanying editorial: as well as the unsafe claims made elsewhere as a direct result of the publication.The first complaint regards the publication of the article itself,

Wednesday, 8 June 2011

Self-explanatory: an email sent to Zoe Mullan and Richard Horton of the Lancet

Email from me to Mullan and to Horton (separately) dated 2nd June 2011:

Dear Miss Mullan
 
Dr Horton has not answered this complaint sent to him 25th April 2011.
 
If I do not receive, personally, a response from him regarding my specific complaints in 7 days, I will be taking these complaints, and concerns about subsequent behaviour from Dr Horton, to the Lancet Ombudsman.
 
I have copied him in to this email. As his apparent assistant and previous spokesperson, will you please ensure he is aware of this email.
 
Many thanks
Angela Kennedy

Thursday, 19 May 2011

From Professor Malcolm Hooper, 18th May 2011

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

18th May 2011


On 17th May 2011 Zoe Mullan, Senior Editor at The Lancet, sent an email to Professor Hooper in response to the complaint he submitted about the PACE Trial article published online by The Lancet on 18th February 2011 and subsequently in the journal on 5th March 2011. In her email, Zoe Mullan wrote: “We asked the authors of the PACE trial to respond to your concerns, which they have duly done. Your complaint and their response were discussed at the highest management level and this group of executive editors was fully satisfied that there were no grounds whatsoever on which to take further action. We attach the response provided to us here. From an editorial perspective, the case is now closed”.

The undated response to Professor Hooper’s complaint by Professors White, Sharpe and Chalder that was sent to Dr Richard Horton (Editor-in-Chief of The Lancet) on behalf of all the co-authors will, in the interests of openness and transparency, be placed in the public domain and will be fully addressed in due course, as will Professor Hooper’s concerns over what he believes is the failure of The Lancet’s editorial process in this instance, but there is one point in Professor White’s letter that is of particular importance, so it is addressed in this initial response.

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”.

The sentence continues by stating that the PACE Trial studied: “CFS defined simply as a principal complaint of fatigue that is disabling, having lasted six months, with no alternative medical explanation (Oxford criteria)”.

This is exactly what the ME/CFS community has been saying from the outset, namely that the PACE Trial was not studying those with ME.

Soon after the Oxford criteria were published in 1991, one of the co-authors, psychiatrist Anthony David, wrote in the British Medical Bulletin: “British investigators have put forward an alternative, less strict, operational definition which is essentially chronic…fatigue in the absence of neurological signs, (with) psychiatric symptoms…as common associated features” (AS David; BMB 1991:47:4:966-988).

Given that ME is a classified neurological disorder (ICD-10 G93.3), there thus ought to have been no dispute that the PACE Trial Investigators were not studying those with ME, but the Investigators have persistently confirmed that they were studying those with ME, for example:

1. The PACE Trial Identifier is clear: “Myalgic encephalomyelitis is thought by most to be synonymous with CFS” (PACE Trial Identifier; 2.1). The cited references for this statement are given as (i) Fukuda K et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med 1994; 121: 953-959; (ii) Sharpe MC et al. A report – chronic fatigue syndrome. JR Soc Med 1991; 84: 118-121; (iii) Wessely SC et al. Chronic fatigue and its syndromes. Oxford, Oxford University Press, 1998; (iv) Working group report to the Chief Medical Officer, www.doh.gov.uk/cmo/cfsmereport 2002 and (v) NHS Centre for Reviews and Dissemination. Interventions for the management of CFS/ME. Effective Health Care 2002; 7(4): 1-12.

2. The two versions of the PACE Trial Protocol (both the Full Protocol and short version that was published in BMC Neurology 2007:7:6) are equally clear; the PACE Trial was: “A randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy”.

3. In the Glossary to the Full Protocol, Professor White et al specifically state that CFS/ME is the official term for the illness described in the “Working Group Report to the Chief Medical Officer (2002) and the MRC RAG Report (2003)”.

4. In the PACE Trial Patient Clinic Leaflet, Professor White et al state: “This illness is also known as post-viral fatigue syndrome, myalgic encephalomyelitis (ME) and myalgic encephalopathy (ME). Medical authorities are not certain that CFS is exactly the same illness as ME…but we will be calling this illness CFS/ME”.

In The Lancet article itself, Peter White et al use the term myalgic encephalomyelitis throughout the text and actually state: “Myalgic encephalomyelitis is thought by some researchers to be the same disorder….Several diagnostic criteria exist for chronic fatigue syndrome and myalgic encephalomyelitis”, thus implying that they had indeed studied those with ME.

Moreover, in the authors’ reply published in the Lancet on 17th May 2011 (The PACE trial in chronic fatigue syndrome – Authors’ reply), Peter White is unambiguous: “…however we defined CFS and myalgic encephalomyelitis, we found that cognitive behaviour therapy and graded exercise therapy provided a significant and clinically useful advantage….”.

Here, though, Professors White, Sharpe and Chalder have categorically stated that the PACE Trial “does not purport to be studying CFS/ME”.

This may explain why so many recruits were not accepted into the PACE Trial on the stated grounds they did not fulfil the Oxford criteria for “CFS” (which according to the Principal Investigators themselves, is not the same as “CFS/ME”).

If the PACE Trial was not studying CFS/ME (as now asserted by Professor White et al), then the results cannot be used by NICE to support its Clinical Guideline 53 for CFS/ME.

NICE, however, announced on 14th March 2011 that there will be no review of CG53 until 2013: “…interventions recommended in the original guideline, such as CBT and GET, were described as the interventions for which there is the clearest evidence-base of benefit. This is supported by the recently published PACE trial….The results of the study are in line with current NICE guideline recommendations on the management of CFS/ME….There are no factors…which would invalidate or change the direction of the current guideline recommendations. The CFS/ME guideline should not be updated at this time”.

Most certainly, this statement by the Principal Investigators that the PACE Trial did not purport to be studying those with CFS/ME raises important issues about the alleged generalisability of the PACE Trial results, given that The Lancet article unambiguously states: “The PACE findings can be generalised to patients who also meet alternative diagnostic criteria for chronic fatigue syndrome and myalgic encephalomyelitis but only if fatigue is their main symptom”.

That The Lancet supports the Principal Investigators’ inconsistent and indefensible position and refuses to engage with clearly articulated complaints must be of concern to anyone interested in the integrity of the scientific process.

Permission to repost.

Wednesday, 27 April 2011

Complaint to the editor of the Lancet regarding the PACE Trial

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/commen
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.htm

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

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
trial's '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>
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