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So Near Yet So Far...

Posted Sep 07 2010 2:42pm


So near yet so far – from Mission Accomplished?

Margaret Williams 7th September 2010

The British Association of CFS/ME (BACME, of which Dr Esther Crawley is
Chair) supports the current NICE Guideline CG53 and its recommendation of
only cognitive behavioural therapy and graded exercise in the management of
ME/CFS. BACME has taken on the role of training NHS staff accordingly, even
though it seems to be accountable only to itself; it is to hold a meeting on
13th-14th October 2010 at Milton Keynes and its provisional programme
affirms that Professor Peter White (Chief Investigator of the MRC PACE Trial
on ME/CFS) will speak about it in a talk entitled “PACE trial: so near yet
so far”. The BACME notice goes on to say that if the PACE Trial outcome
results are not published by then, Professor White will present the design,
progress and baseline data from the trial.

From over 2,000 pages of information obtained under the Freedom of
Information Act, much is already known about the design and progress of the
PACE Trial (
<> ), including the fact
that its entry criteria were intentionally broad (“We chose these broad
criteria in order to enhance generalisability and recruitment”; Trial
Identifier 3.6). Despite the use of such broad entry criteria, there were
serious recruitment difficulties, so the entry criteria were broadened even
further when on 14th July 2006 Peter White sought approval from the West
Midlands MREC to write to GPs imploring them to send anyone with “chronic
fatigue (or synonym)” for entry into the PACE Trial, thereby opening the
trial to anyone who was merely chronically tired.

Given the customary requirement for study cohorts to be as homogeneous as
possibly, this seems to defy logic: how can the Wessely School’s long-held
desire to “clarify the role that psychiatric disorders have in fatiguing
illness” (Ann Int Med 1994:121:12:953-959) and their inclusion of persons
with psychiatric disorders possibly restore to health people with the
neuroimmune disease ME/CFS who are allegedly the subjects under study, any
more than it would be able to restore to health people with multiple
sclerosis or motor neurone disease?

The fundamental point is that the PACE Trial interventions are not designed
to offer psychological support to those coping with life-shattering disease,
but to comprehensively disabuse them of their belief that they suffer from a
serious organic disease. If the aim of the PACE Trial is merely to indulge
the Wessely School psychiatrists’ unproven beliefs (which Professor Michael
Sharpe has already admitted are “without theoretical foundation” (

<> ), on what
grounds did it gain ethical approval?

How can the results of a trial that was deliberately designed to conflate
people with behavioural disorders, idiopathic fatigue, fibromyalgia and
people with ME/CFS (characterised by immunological, neurological, metabolic,
cardiovascular, respiratory and musculo-skeletal dysfunction, the cardinal
symptom being post-exertional exhaustion accompanied by malaise) be equally
applicable to and effective for such diverse disorders?

If the role of psychiatric morbidity in “fatiguing illness” is being
studied, then why was the trial designed to exclude people with multiple
sclerosis who definitely experience profound and disabling fatigue?

The answer, of course, is that the PACE Trial limits the study to those
people suffering from disorders that the Wessely School deem to be “mental”
disorders.

Notably, in an exchange of correspondence (Conversing with Professor Simon
Wessely: (

with-professor-simon-wessely-part2/), Wessely states: “…it is essential in
any study to make it clear exactly where your subjects come from – without
that it is impossible to generalise from any report/paper/treatment. This
not a new observation – you will see that we pointed that out in 1996, and
have continued in all papers to make that distinction abundantly clear”.

Many would challenge Wessely’s assertion that his study cohorts have always
been strictly defined; moreover, is it not curious, given that he is in
charge of the Clinical Trials Unit for the PACE Trial, that Wessely
apparently saw no need to exercise such care in the PACE cohort? Does this
not mean that, on Wessely’s own admission, if a cohort is heterogeneous
(which the PACE Trial undoubtedly is), then the conclusions cannot be
generalised and so will have no clinical relevance and thus be a waste of
tax-payers’ money?

It has already been shown that the PACE Trial Investigators apparently did
not adhere to good research practice on numerous other counts also,
including their apparent failure to observe either the AGREE Instrument or
the Declaration of Helsinki, and there are consequential concerns about how
meticulously they will adhere to the CONSORT Statement. CONSORT
(Consolidated Standards of Reporting Trials) was developed by a group of
scientists and editors in 1996; it was updated in 2001 and again in 2010 and
it consists of a checklist that authors are recommended to use for reporting
a randomised controlled trial (RCT). It is based on the premise that “The
whole of medicine depends on the transparent reporting of clinical trials”
and its authors note that trials with inadequate methods are associated with
bias, especially exaggerated treatment effects, and that reporting is not
only often incomplete but also sometimes inaccurate. They point out that“Biased results from poorly designed and reported trials can mislead
decision making in health care at all levels, from treatment decisions for a
patient to formulation of national public health policies….Bias jeopardises
even RCTs, however, if investigators carry out such trials improperly…The
methods used should be complete and transparent so that readers can readily
differentiate trials with unbiased results from those with questionable
results….We encourage peer reviewers and editors to use the CONSORT
checklist to assess whether authors have reported on these items” (D Moher /
D. Altman et al; BMJ 2010:340:c869). One of the items on the CONSORT
checklist relates to trial design, with particular emphasis on important
changes to eligibility criteria that are made after trial commencement (as
occurred in the PACE Trial) – and the reasons for them.

Furthermore, as an experienced member of a Research Ethics Committee who is
familiar with the PACE Trial documentation has pointed out, the PACE Trial
is a classic example of over-measurement of variables (ie. it measures too
many variables so it is almost inevitable that the data will show spurious
“positive” results which in fact have no clinical meaning).

These are very serious matters that, as Chief Investigator, Professor White
will need to address with total transparency sooner rather than later.

In response to a previous formal complaint about the PACE Trial made in 2004
by a former MRC grant-holder, Elizabeth Mitchell, MRC External
Communications Manager, wrote on 15th November 2004 about the PACE and FINE
Trials: “The design of these trials have been judged by international and UK
peer review to be appropriate for delivering the trial objectives, including
use of the broad inclusion criteria”.

This is undoubtedly so, because if a proposal is sent for peer review to
those who hold similar views to the Investigators, those reviewers will
obviously support it. The real question is – what exactly were the “trial
objectives”? It was already known that the interventions used in the trial
are at best of little help and at worst are damaging to those with ME/CFS
(ie. the alleged target group) and that the interventions being studied do
not reduce either fatigue or disability in such patients. Was this in
reality an elaborate exercise for the benefit of the DWP and the
medical/permanent health insurance industry?

It is notable that Dr Cathie Sudlow, an Edinburgh neurologist who
collaborates with Professor Michael Sharpe, wrote in the BMJ (BMJ
2010:340:c1260) about the discovery of the retrovirus XMRV in relation to
ME/CFS in the Lombardi/Mikovits et al paper that was published in Science on
9th October 2009: “The role of reviewers here is crucial…their contribution
should be publicly recognised and valued by journals and by the scientific
community as part of the scientific record. This can surely only happen if
reviewers are always openly identified and their comments published”
(emphasis added). Indeed, but will this apply to the PACE Trial? Would it
expose bias if so?

Given the recent findings of the “dramatic association” of a family of
retroviruses with ME/CFS that have been published in both Science and PNAS (
), on what logic or evidence
do the PACE Trial Principal Investigators Professors Peter White, Michael
Sharpe and Trudie Chalder continue to rely to support their belief that the
Trial will confirm that “behavioural restructuring” can cure such seriously
sick patients (this is what the Trial manuals claim )? If the PIs do not hold
such views, then why have they received £5 million to test those beliefs?

“So near yet so far”: is it the case that the Wessely School were so near
to achieving their goal of showing that ME/CFS is a somatisation disorder,
using the PACE Trial data, only to be thwarted by the publication of papers
in Science and PNAS showing a strong association of a retrovirus with
ME/CFS, making their goal scientifically untenable?

Notwithstanding, the way seems to be being paved by the Wessely School for
further disparaging attacks on those scientists who have found retroviral
involvement in some ME/CFS patients and for yet more dismissal of the
significance of those findings.

Whilst the ground-breaking retroviral link published in PNAS on 23rd August
2010 was announced in over 150 outlets world-wide, including Russia and
Latvia, and whilst it was deemed to be of such importance that it featured
on the front page of the Wall Street Journal, the UK media remained
deafeningly silent and there was effectively a news black-out. It was not
until after 31st August 2010 that the Science Media Centre (through which
all UK media announcements about medical/scientific issues must now
seemingly pass, and where Professor Simon Wessely is a member of the
Scientific Advisory Panel) published a statement (apparently back-dated to
23rd August 2010) that downplayed the significance of the retroviral
association with ME/CFS.

Entitled “Expert reaction to PNAS study on viral sequences found in blood of
chronic fatigue patients” and quoting two UK virologists (Professors Robin
Weiss and Myra McClure), the SMC press release was dismissive: Professor
Weiss stated: “It is based on small numbers….Let’s hope it is not another
claim like MMR…which didn’t hold up (untrue: the UK High Court recently
ruled that the MMR vaccine is not safe, which the UK Government has been
forced to concede: Sunday Times, 29th August 2010), but I am sceptical of
the claim…One should also bear in mind that no less than 4 negative reports
on this topic (failing to find a retrovirus link) have been published this
year from reputable groups in the UK, the Netherlands and at the Centre for
Communicable Diseases & Prevention in Atlanta, USA” and Professor McClure
stated: “…it is important to realise that this group have not detected the
virus (XMRV) that claimed media attention after the publication of
Lombardi’s paper in Science last year. They describe murine leukaemia virus
(MLV)-related sequences that are genetically distinct from XMRV….Several
other groups (including Professor McClure’s own group)…have employed the
same experimental protocol, yet have consistently failed to detect any
retrovirus in CFS patients”.

The SMC has an established track record of down-playing any association of
retroviruses with ME/CFS (for example, and
). Given the disparaging tone of the latest SMC press
release, it is little wonder that the UK media did not bother, even
belatedly, to publish anything about it. It is possible that the SMC’s
intention was to ignore the game-changing discovery entirely, but after it
was publicly asked by a contributor to an internet group why this important
breaking news had not been mentioned except for a low-key article in the
Daily Mail, the SMC perhaps felt obliged to note it, but did so as
dismissively as possible.

Could this be because nothing is to be allowed to detract from the PACE
Trial findings that cognitive restructuring – including graded aerobic
exercise -- are likely to be claimed to be restorative for patients with
ME/CFS?

It is interesting that, over the years, Professor Wessely has repeatedly
asserted that he is no longer involved with the politics of CFS research,
most recently at the beginning of August 2010 (

with-professor-simon-wessely-part2/
<
-with-professor-simon-wessely-part2/> ), yet at the first sign of a
significant threat to his model from the Whittemore Peterson Institute, he
rushed out a paper co-authored by Professor Myra McClure that claimed
effectively to negate the WPI findings.

In the same series of correspondence, Wessely states on the record: “At the
time of writing I can say with my hand on my heart that I believe that the
treatments that we recommend and use in our clinic are currently the best
there is – and nothing i have seen, or read about, suggests otherwise”.
Retroviral involvement in ME/CFS notwithstanding, might this be taken to
indicate what the PACE Trial results will conclude?

This firm statement from Professor Wessely (ie. that nothing he has seen or
read suggests other than that his favoured behavioural interventions are the
best treatment for ME/CFS) seems to indicate that, as noted by the person
from Australia who posted the very revealing exchange of correspondence,
Wessely’s comments are a classic case of the Semmelweis reflex, defined as
“the tendency to reject new evidence that contradicts an established
paradigm”, and s/he commented about Wessely’s stance: “Science works by new
evidence replacing existing paradigms. When this new evidence is presented,
it is a fallacy to reject it with the argument that it interferes with an
existing paradigm…if all scientists used Wessely’s logic …then there would
be no new scientific discoveries”. Wessely maintains that the XMRV research
fails to model the role that childhood abuse, psychological factors and
other infections may play in the illness, whilst also confirming that for
the last 21 years he has promoted his own theory that the “cognitive
behavioural model” is a better explanatory model for chronic ME/CFS than the
chronic viral paradigm that dominated at that time (and which many believe
he was instrumental in suppressing).

That patients with ME/CFS have been left with no alternative but to suffer
from on-going viral illness for the last 21 years and have been deprived of
essential financial support because of the dominant influence of certain
psychiatrists is deplorable and may be recorded in future annals of medicine
with abhorrence and disbelief.

A recent internet post by “XMRV Global Action” announcing that Francis
Collins, Director of the US National Institutes of Health (who oversees an
annual budget of more than $31 billion) is to open the First International
XMRV/MLV Conference on 7th September 2010 noted that this means the NIH are
taking XMRV/MLV very seriously indeed, and that there is an element of
potential scandal, given that people with ME/CFS have been complaining of
profound viral symptoms for decades (and dropping dead from viral
cardiomyopathies and rare lymphomas) while being derided as hypochondriacs (
!/pages/XMRV-Global-Action/216740433250?ref
=ts
<!/pages/XMRV-Global-Action/216740433250?re
f=ts> ).

Yet more evidence has emerged in the UK that the Wessely School’s various
attempts to neutralise what they may consider to be inconvenient findings
simply do not withstand logical analysis and their contemptuous dismissal of
the biomedical research will no longer carry any weight, because their
“cognitive behavioural model” has been dealt what may be a fatal blow.

Whilst there are no children involved in the PACE Trial, paediatrician Dr
Esther Crawley is about to start a study looking at the effect of the
Lightning Process on children aged from 8 to 18 to see if sufferers can be
trained to think differently about how ill they feel and so increase their
exercise levels, but an article in the current issue of the American Medical
Associations’ journal “Archives of Paediatrics and Adolescent Medicine”
2010:164(9):817-823 (Biochemical and Vascular Aspects of Paediatric Chronic
Fatigue Syndrome/Myalgic Encephalomyelitis; G. Kennedy et al:) shows how
unsuitable such a study may be.

There are thought to be about 15,000 children in the UK with ME/CFS and a
team from Dundee that was funded by ME Research UK (MERUK) and The Young ME
Sufferers (TYMES) Trust has found abnormalities in the blood of all the
children with ME/CFS tested but not in controls, the results being similar
to those previously found in adults with ME/CFS and consistent with an
activated inflammatory process.

Professor Jill Belch from the Vascular and Inflammatory Diseases Research
Unit, Ninewells Hospital and Medical School, Dundee, explained this new
research on the BBC Radio 4 Today programme on 7th September 2010, saying
that they have demonstrated two important findings, the first being an
abnormal level of an inflammatory chemical in the blood and that this is
matched by abnormal white blood cell behaviour; she explained that this is
important because “finding an abnormality is halfway to finding a
treatment”. The second finding, said Professor Belch, is that ME/CFS is a
physical abnormality, and this is important because “there has been some
question in some peoples’ mind whether this disease might actually be a
disease of the mind, and I think finding an abnormality reassures us that
this is a genuine physical illness”. The interviewer (Sarah Montague)
responded by asking “Because so many have questioned whether ME even
exists?”, to which Professor Belch replied: “That’s absolutely right”.
Professor Belch went on to say: “These children have a terribly damaged
lifestyle, and if you add disbelief on to that, the parents don’t know
whether to believe the child, (and) the doctors don’t know”. Sarah Montague
summarised the findings, saying: “What you’ve found is what happens to a
body that’s reacting to a virus?”, to which Professor Belch replied: “That’s
correct”, adding: “There is no doubt that once you have an abnormality to
target, treatments can follow” (
).

Commenting on the Dundee research, Dr Neil Abbot, Director of Operations at
MERUK, said: “The study undoubtedly adds greater scientific weight to the
existence of a condition which, sadly, many still fail to acknowledge in
spite of its severity” (
).

The importance of this study cannot be over-emphasised because of the
potential long-term consequences for cardiovascular disease and because, as
Dr Abbot points out, the white blood cells are releasing an excessive amount
of highly reactive free radicals, possibly from exercising muscle (which
would contra-indicate incremental aerobic exercise) and the white blood
cells provide evidence of “a persistent or reactivating viral infection
triggering apoptosis of white blood cells”.

Many people around the world believe that the Wessely School’s “cognitive
behavioural model” of ME/CFS (which includes the use of incremental aerobic
exercise) has been built on sand, not science. Wessely’s own recent
comments, together with the now irrefutable evidence of viral involvement in
ME/CFS, can only have assisted the cognitive behavioural model’s (long
overdue) disappearance from the discipline of medicine.

It may be coincidence, but a video is currently circulating on the internet
featuring Francis Collins, Director of the NIH, singing “The Times They Are
A-Changin’ “ on Capitol Hill (Rock Stars of Science
<> &forumid=331851
).

The times are indeed changing for those with ME/CFS because the stranglehold
of the Wessely School has finally been severed but they will, naturally, go
down fighting because their professional careers in relation to ME/CFS have
been shown to be scientifically invalid, a record of which no-one could be
proud.

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