The PACE Trial - Psychiatrists spinning out of control.

Some Background In February 2011, the Science Media Centre (SMC) hosted a press conference

for the publication in The Lancet of the results of the PACE Trial research into treatments for M.E. and CFS.

The research took 6 years and cost UK tax payers £5 million. 640 Participants received either Cognitive Behaviour Therapy (CBT); Graded Exercise Therapy (GET); Adaptive Pacing Therapy (APT) or Specialist Medical Care (SMC – the Control Group).

CBT and GET were based on theories that M.E. and CFS are ‘deconditioning’ and ‘fear avoidance’. Treating these conditions is simple and effective. They represent the basic work that any psychologist or occupational therapist might undertake.

The PACE Trial results (The Lancet, Feb 2011) for ‘improved’ show that Graded Exercise Therapy (GET) had an effect for 16% and Cognitive Behaviour Therapy (CBT) for 14% compared to the control group. The results for ‘normal ranges’ show that GET had an effect for 13% and CBT for 15%.

These results produce a ‘number needed to treat’ figure of 7. In other words, if 7 people are treated with one of these therapies – one of them will improve but the remaining 6 will not get any significant benefit.

Some Concerns Professor Hooper et al remarked, “The indisputable commitment of so many

members of the PACE team to the insurance industry (especially Professors White and Sharpe in their roles as Chief Medical Officer to so many insurance companies) is a significant cause for concern, since their continued recommendation of CBT and GET and their insistence that ME/CFS is a functional (mental) disorder benefits the insurance industry for which they work to the prejudice of patients.” (http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.htm)

Professor Peter White, the chief investigator of the PACE Trial, also does work for the Department of Work and Pensions (DWP) who co-funded the PACE Trial. The only clinical research that the DWP have ever funded.

The Science Media Centre which hosted the press conference declare: “The overall goal of the Centre is to help renew public trust in science by working to promote more balanced, accurate and rational coverage of the controversial science stories that now regularly hit the headlines”. (http://www.sciencemediacentre.org/uploadDir/536adminconsultation_report.pdf)

The Science Media Centre ‘expert’ for M.E. and CFS news stories is Professor Simon Wessely who was in the PACE Trial management group. For many years he has claimed that M.E. and CFS are psychological illnesses. He stated: “I will argue that ME is simply a belief, the belief that one has an illness called ME” (Microbes, Mental Illness, The Media and ME: Institute of Psychiatry, London, 12 May 1994)

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News Coverage of the PACE Trial – Mistaken or Misled?The Science Media Centre press conference resulted in media statements that are not supported by the research findings. Here are a few Headlines:

The Daily Mail: Got ME? Fatigued patients who go out and exercise have best hope of recovery, finds study The Independent: Got ME? Just get out and exercise, say scientistsThe Guardian: Study finds therapy and exercise best for METhe Telegraph: Exercise and therapy can help ME sufferers, study claimsThe Daily Express: TRIAL OFFERS HOPE FOR ME SUFFERERSThe Daily Record: Exercise and therapy can reverse effects of METhe Daily Star: TRIAL OFFERS HOPE FOR ME SUFFERERSReuters: Pushing limits can help chronic fatigue patients

IT IS IMPOSSIBLE to reconcile these headlines with the fact that the PACE Trial results as published in The Lancet showed that GET and CBT only had an effect for around 15% of participants.

How could the press get it so wrong? After all, they got their information direct from the PACE Trial researchers via the Science Media Centre; the centre for ‘balanced, accurate and rational coverage’ of science. Professors Wessely, White, Sharpe and Chalder must have had complete control over the information given to the press.

Some Points that did Not Make Headlines Professor White the chief investigator stated in contradiction of the Trial

Protocol and The Lancet publication, that the PACE Trial was not studying “CFS/ME”. He claims they were only studying people with fatigue as a main symptom. (http://www.meactionuk.org.uk/Comments-on-PDW-letter-re-PACE.htm)

The criteria of ‘fatigue’ does not define M.E. or CFS according to the NICE Guidelines (2007), the CMO Report (2002) and all other authorities on these illnesses.

The PACE Trial researchers were aware that using lax criteria for CFS could improve the outcome of their therapies. They reference Joyce, Hotopf and Wessely who stated: “As the definition becomes more stringent the prognosis appears to worsen.” (PACE Protocol reference 9).

Severely ill patients were excluded from participation – these make up around 25% of patients. The PACE Trial researchers were aware that excluding severely ill patients could improve the outcome of their therapies. They reference Effective Health Care which states: “The prognosis tends to be worse for severely ill patients than for less severely ill patients”. (PACE Protocol reference 5).

The FINE Trial published a year earlier, established that rehabilitation therapies do not benefit severely ill patients. Therefore if the PACE Trial had included 25% of severely ill patients to reflect the general patient population it is reasonable to project that the apparent treatment-effect in the PACE Trial would only have occurred in 12%, instead of 15%; and given the limitations of RCTs, a realistic ‘need to treat’ figure in general medical practice would probably be at least 10.

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The PACE Trial has not demonstrated any significant benefit with GET or CBT. Lead researcher Professor Michael Sharpe told ABC Australia: “What this trial isn't able to answer is how much better are these treatments than really not having very much treatment at all?” (http://www.abc.net.au/radionational/programs/healthreport/comparison-of-treatments-for-chronic-fatigue/2993296)

Which is incredible given that this research cost UK Tax-payers £5 million and the Trial Protocol claimed: ‘The main aim of this trial is to provide high quality evidence to inform choices made by patients, patient organisations, health services and health professionals about the relative benefits, cost-effectiveness, and cost-utility, as well as adverse effects, of the most widely advocated treatments for CFS/ME.’

Hooper observed: “…adverse event deemed by trial scrutinisers to be “non-serious” were CBT Group 89%; SMC and GET groups 93%; and APT Group 96%.” And: “… we have no idea how many of the 3,002 adverse events that were deemed “non serious” may have been reactions to the trial interventions.” (http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.htm)

Sir Michael Rawlins (as Chair of NICE) stated that, “we need a new approach to analysing clinical evidence”. He observed that Randomised Controlled Trials, “are often carried out on specific types of patients for a relatively short period of time [snip]. There is a presumption that, in general, the benefits shown in an RCT can be extrapolated to a wide population; but there is abundant evidence to show that the harmfulness of an intervention is often missed in RCTs.” (http://pressrelease.rcplondon.ac.uk/Archive/2008/Attack-on-traditional-ways-of-assessing-the-evidence-of-therapeutic-interventions)

The PACE Trial relied almost entirely on subjective measures (questionnaires). This is a contradiction. The Trial treatments GET and CBT were based on theories that participants are not physically ill but are incapable of accurately interpreting their own symptoms because of phobia and hysteria. Yet the opinions of these supposedly delusional participants are considered reliable to provide data for a clinical trial.

More ConcernsThe PACE Trial researchers modified benchmarks and entry criteria, cancelled or misapplied measures and changed scoring methods during the Trial. These changes had the effect of damaging generalizability, favoured the treatments being tested, eliminated objective measurements and created ludicrous anomalies:

People originally disqualified from participation were later allowed to join the Trial. Patients with a completely different illness from the target group were allowed to join (fibromyalgia).

Because of moveable benchmarks, it was possible for a participant to join the trial, deteriorate, yet still fall within the modified definition of ‘normal range’.

Improvements from GET and CBT were so small that many patients that met the researcher’s chosen definition of ‘normal functioning’ were still more disabled than people with other serious diseases.

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The Trial Protocol stated that actigraphy measurement would be used at the start and end of treatment. The investigators cancelled this objective test as an outcome measure, claiming it was too much of an imposition even though all the participants wore the monitor at the start of their testing.

A 6 Minute Walk Test was the only objective measure used at the start and end of the treatment. However, the researchers did not follow the protocol for the 6 Minute Walk Test. To obtain reproducible data with this test a practice walk is required but this was omitted without explanation and without being declared.

For those who received CBT the mean Walk Test distance was 354 metres. This is 1.5 metres LESS THAN THE CONTROL GROUP.

For those who had undergone GET, the mean distance was 379 metres (an increase of 67 metres from baseline). Patients with chronic obstructive pulmonary disorder are able to walk on average 60 metres further than participants that received GET.

At 52 weeks the average increase for the CBT group was 21 metres, to an average 354 metres. This distance is 75 metres LESS than the ‘baseline’ (before any treatment) distance in Sharpe et al 1996, Cognitive behaviour therapy for the chronic fatigue syndrome: a randomised controlled trial (PACE Protocol reference 25). If this group’s walking distance had improved 3.5 times more than it did, the average participant would still be disabled enough to have entered Sharpe et al’s CFS research.

After CBT or GET, PACE Trial participants (whose average age was under 40) did not even achieve a six minute walking distance of 518 metres which is lower than average scores for healthy people aged 50-85 years. Patients with Class III heart-failure score higher than PACE Trial participants.

In comparison to other outcome data, around 20% more participants have no data for the Walk Test. No explanation is given for the missing data.

The Lancet Spins the Dross Given the above, it is strange that Richard Horton the editor of The Lancet

(which published the PACE Trial), told ABC’s Health Report about the PACE Trial researchers: “…So they were really stepping back and comparing two philosophies, not just two treatments, two philosophies of what chronic fatigue syndrome was” (http://www.abc.net.au/radionational/programs/healthreport/comparison-

of-treatments-for-chronic-fatigue/2993296);

The design of the PACE Trial actually avoids comparison of the two ‘philosophies’ because it made no measures of physiological responses and even refused to record participant’s levels of activity. The design of the trial excluded objective measures necessary to make a comparison; necessary to establish harms and benefits; and necessary to conduct credible medical research.

Horton claims that the PACE researchers were objective and presumably attributes similar objectivity to himself. If this is so, then why did the significant fact that only 15% of participants benefited from GET and CBT, end up buried in the complex text of The Lancet article, requiring the

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reader to carry out their own mathematical calculations to discover a finding of such importance?

Horton went on: “This is why I think 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.”

Impartial? The headlines reproduced above do not appear impartial and they certainly do not reflect the findings of the research. They originate from the researchers themselves via the Science Media Centre press conference.

The real ‘mirage’ was the concealment of important research findings in The Lancet article. This contributed to the misperception that the PACE Trial showed that GET and CBT successfully treat M.E. and CFS. Horton has bought into this mirage wholesale and has engaged in actively reinforcing the illusion.

Horton continued: “The issue here which I still fail to understand is that nobody is claiming that chronic fatigue syndrome is an invented illness. It's taken just as seriously as any other condition.”

If CFS is ‘taken just as seriously as any other condition’, perhaps Horton can explain the research funding figures for 2010 from the US National Institutes of Health (dollar amounts in millions) (http://report.nih.gov/categorical_spending.aspx):

362 Prostate Cancer 277 Asthma 151 Multiple Sclerosis 78 Crohn's Disease16 Psoriasis11 Myasthenia Gravis6 Chronic Fatigue Syndrome(ME/CFS)

ME/CFS affect 2.5 to 4 times as many people as Crohn’s Disease yet the latter gets 13x more research funding. ME/CFS affect 2 to 3 times as many people as Multiple Sclerosis. Yet the latter gets 25x more research funding.

Horton also remarked on criticisms of the PACE Trial: “This isn't a purely scientific debate; this is going to the heart of the integrity of the scientists who conducted this study.”

There are serious and valid questions about the conduct and reporting of the PACE Trial. The researchers and Horton himself have failed to address these concerns. They appear to avoid debate with those that present awkward questions and the people that pay the price of their authoritarian terms of engagement are the patients.

An ‘utterly impartial perspective’ The Daily Telegraph, a generally respected UK daily newspaper wrote about

the PACE Trial and remarked: “Prof Willie Hamilton, a GP in Exeter, added: “At least half of patients improved with CBT or GET.””

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As pointed out already, only 15% improved with CBT or GET compared to the Control Group. Perhaps this ‘Professor’ does not understand the purpose of having a Control Group in a controlled clinical trial and is unaware that a treatment effect is established by comparing the Treatment Group with the Control Group.

Of interest may be that this ‘GP in Exeter’ is Chief Medical Officer for three permanent health insurance companies -- Exeter Friendly Society, Liverpool Victoria and Friends Provident – and he categorises ME/CFS as a functional disorder. (http://www.meactionuk.org.uk/COMPLAINT-to-Lancet-re-PACE.htm).

The Science Media Centre declare about themselves:“…the Centre will be free of any particular agenda within science and will always strive to promote a broad spectrum of scientific opinion – especially where there are clear divisions within science. It will not shy away from promoting voices that are critical of particular aspects of science.” (http://www.sciencemediacentre.org/uploadDir/536adminconsultation_report.pdf)

And their Press Release for the PACE Trial includes [emphasis added]: “Dr Alastair Miller, Consultant Physician at Royal Liverpool University Hospital, Clinical lead for CFS services in Liverpool, Independent assessor of trial safety data for PACE trial and Principal Medical Advisor, Action for ME, said:

"This trial represents the highest grade of clinical evidence – a large randomized clinical trial, carefully designed, rigorously conducted and scrupulously analysed and reported. It provides convincing evidence that GET and CBT are safe and effective and should be widely available for our patients with CFS/ME.”

Dr Miller, medical adviser to Action for ME Dr Miller appears to be unaware that for many doctors and scientists, “the

highest grade of clinical evidence” requires substantial, reliable and consistent OBJECTIVE data. Graphs and tables might look impressive, but when they are based on SUBJECTIVE data they will never represent, “the highest grade of clinical evidence”.

As for “GET and CBT are safe and effective”. Effective: “producing a decided, decisive, or desired effect ” (Merriam-Webster). The PACE Trial’s own data produced a need to treat figure of 7. When only 1 in 7 patients benefit from either of these treatments the result does not meet the definition of ‘effective’.

Dr Miller is medical advisor to the charity Action for ME (AfME) since May 2010. Unlike the other main UK charities, AfME cooperated with the PACE Trial from its early days. The PACE Protocol remarks that the PACE Trial was designed in collaboration with AfME. The Chief Executive of AfME at the time, Chris Clark, was a member of the Trial Steering Committee. AfME received over £3,000 from the PACE Trial funds.

Dr Miller presented at the Royal Society of Medicine Conference on CFS in 2008. He told the conference about CFS: “obviously a lot of psychological factors acting either to precipitate or, or perpetuate and predispose to this condition".

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Dr Miller tried a few jokes at the conference, "… Lerner's study on Ganciclovir, um, possibly suggested some symptomatic benefit, but two patients, but they were doing endomyocardial biopsies on these patients um, and the -- some of the people who are pushing for a lot of -- biological, er, research maybe ought to be put-off [laughing] by some of these things; and the study was not surprisingly was -- terminated prematurely."

Dr Lerner’s research included heart tissue biopsy. They discovered that some CFS patient’s heart tissue was ‘friable’ (crumbly) – a significant and disturbing finding. Lerner’s team found that this change in the cardiac tissue made it difficult to stop the bleeding after biopsy. They stopped the tests and publicised this adverse event.

It should be noted that the audience did not appear to find Miller’s anecdote quite as amusing as he did himself. Perhaps some of them were aware of Lerner’s research and did not find the thought of an unfortunate patient having heart tissue that falls to pieces easily a cause for amusement.

Dr Miller had more success with his next joke, “And Interferon's been tried. I use a lot of interferon for treating um, for treating viral hepatitis and it does make people feel pretty rough so, er, I thought maybe interferon would be a good thing because you could give it and then when you stop giving it people feel so much better [laughing] - they probably thought they've been cured. [Audience laughter]”

That one did better but frankly, Miller’s future as a stand-up comedian looks bleak. Perhaps he will do better in monitoring safety issues, independently, objectively and effectively. After all, he may make jokes about serious adverse events in research but that does not mean that he does not also take them seriously.

In March 2008 Miller informed a correspondent [emphasis added], “The reality right now is that we do not have any evidenced (sic) based approaches other than CBT and GET to help our patients and these techniques are helpful to many of our patients – not everyone and I do accept that in some cases they may worsen the situation but that is true of many conditions and many therapeutic interventions.” (http://readmeukevents.wordpress.com/2008/03/21/correspondence-with-dr-alastair-miller-speaker-rsm-cfs-conference/)

It is impossible to guess how many ‘some cases’ would be, but in the PACE Trial 320 participants received GET or CBT and it seems incredible that none had adverse effects attributable to the therapy requiring warnings to be attached to these therapies.

It is surely true that ‘many therapeutic interventions’ can worsen a patient’s condition; though when this is the case, doctors and patients are generally aware of the risks because discovering this is an important responsibility of research and dissemination of the findings; as well as being obligatory in respecting patient autonomy.

There are numerous patient surveys conducted and published by the major UK M.E. and CFS charities that provide very convincing evidence of low efficacy and high risk with GET and CBT. These surveys have received hundreds and

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sometimes thousands of responses. But the awkward truth is that they represent nothing more than the opinions of patients. Yet this being so, why does Dr Miller think that the opinions of PACE Trial patients constitute, “the highest grade of clinical evidence”?

The only remotely objective evidence in the PACE Trial is the 6 minute walk test. The data from this test shows that GET and CBT are practically useless, so this cannot be what Miller is referring to as being, “the highest grade of clinical evidence”. He must be referring to the opinions of the participants.

Whose opinions do you think might be more reliable?

A patient in a clinical trial who is receiving a lot of attention, believes they are being helped, feels indebted for the free treatment they are getting, is grateful to a therapist and is being urged to think more positively about their illness and to minimise the importance of their symptoms and disability

Or, a patient filling in a survey who may have had the therapy much earlier, has no obligations or loyalties and has had time to reflect on exactly what the therapy achieved for them

The Highest Grade of Clinical Ignorance? White et al and safety monitor Miller, seem to view M.E. and CFS patients as

somewhat loony. The ‘good’ thing about tampering with the minds of loonies is that if you screw-up and make things worse nobody is going to blame you. As remarked earlier, if PACE Trial participants get more ill, they can simply be considered more hysterical and you cannot blame someone who was trying to help them.

Serious problems could arise if PACE Trial participants were found to be physically ill and not loony at all. The ethical and legal implications could be far-reaching.

Imagine trying to convince people that are impaired by a disease so severe that it is described by some experts as worse than almost any other chronic illness; that there is nothing wrong with them. Imagine taking a healthy mind which may be struggling heroically to maintain coping through dreadful pain and illness, and screwing-up that mind until the person does not know what they think or feel anymore. Imagine trying to convince a well-balanced person that they are a loony, so that you can do a therapy on them to make them rational.

I have not seen any evidence that these risks have even been considered nor trial data referring to these dangers. IMO this omission reflects a prejudice when it comes to M.E. and CFS. These patients, their illness and their disability are not taken seriously. You can do what you like to them and publish any old rubbish about them and it does not matter because you cannot be held to account.

Years ago, a doctor appealed to wessely-school type theorists to consider, ‘What if you are wrong?’ Perhaps now we have an answer. The PACE Trial has comprehensively undermined wessely-school theories but the response to this

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important and humbling evidence appears to be: if you are wrong, spin the evidence.

The PACE Trial discredits the researcher’s theories Even after 20 years of theorising and experimenting with treatments and with

£5 million spent on testing them. Even with willing and cooperative participants and 6 years to get it right. Even though severely ill patients were excluded and even though the researchers contrived or modified ratings, thresholds, entry criteria, objective measures. Viewed objectively, GET and CBT failed to treat M.E. or CFS.

The only possible conclusion is that GET and CBT are of no significant benefit to M.E. or CFS and any further research into these non-treatments would be an unjustifiable waste of resources.

The Lancet proclaim: “When Thomas Wakley founded The Lancet in 1823, he announced "A lancet can be an arched window to let in the light or it can be a sharp surgical instrument to cut out the dross and I intend to use it in both senses". This philosophy remains at the heart of the journal today.” (http://www.thelancet.com/lancet-about)

One wonders what Wakley would make of The Lancet abandoning science for spin?

Peter KempOct 2012

For links to further information please see:http://www.investinme.org/Article400%20Magical%20Medicine.htm

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