Wednesday, April 27, 2011

Angela Kennedy's complaint to the editor of the Lancet, Dr Richard Horton, regarding the PACE trial


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

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:

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:

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

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

"...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

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

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

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

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

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

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

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

"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

"...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

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

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

Yours sincerely,

Angela Kennedy

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