ME/CFS and the PACE trial

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Here I review the disastrous trial known as the ‘PACE trial’. This updates a post from several years ago.

Readers may also be interested in seeing the Special Issue on the PACE trial in the Journal of Health Psychology (2017).

Review of the evidence indicates that none of the Wessely School’s hypotheses about the causes of ME/CFS are supported by the science (see here, here and here). Under these circumstances it would be scientifically impossible for ME/CFS treatments based on these incorrect principles to actually work. Only if there is a ‘fix’ and evidence is craftily manipulated by scientific sleight-of-hand could the therapies be made to look effective.

Which is exactly what has happened.

ME/CFS patients have known the truth for donkey’s years. Only the perpetrators of the ‘CBT/GET Illusion’ have claimed otherwise.

I review here the PACE trial and present a few details of an exposure by Carolyn Wilshire, Tom Kindlon, Alem Matthees and Simon McGrath (2017), which reveals the true null effect.

What was the PACE Trial?

Rarely in the history of clinical medicine have doctors and patients been placed so bitterly at loggerheads. The dispute had been a long time coming. Thirty years ago, a few psychiatrists and psychologists offered a hypothesis based on a Psychological Theory in which ME/CFS is constructed as a psychosocial illness. According to the Wessely School, ME/CFS patients have “dysfunctional beliefs” that their symptoms are caused by an organic disease. The ‘Dysfunctional Belief Theory’ (DBT) assumes that no underlying pathology is causing the symptoms; patients are simply being ‘hypervigilant to normal bodily sensations‘ (Wessely et al., 1989; Wessely et al., 1991).

The Wessely School Theory assumes that the physical symptoms of ME/CFS are the result of ‘deconditioning’ or ‘dysregulation’ caused by sedentary behaviour, accompanied by disrupted sleep cycles and stress. Counteracting deconditioning involves normalising sleep cycles, reducing anxiety levels and increasing physical exertion.  Attentional biases also divert the patients towards their symptoms.

To put it bluntly, the DBT asserts that ME/CFS is ‘all in the mind’.  Small wonder that patient groups have been expressing anger and resentment in their droves.

Top-Down Research

‘Top-down research’ uses a hierarchy of personnel, duties and skill-sets. The person at the top sets the agenda and the underlings do the work. The structure is a bit like the social hierarchy of ancient Egypt. Unless carefully managed, this top-down approach risks creating a self-fulfilling prophecy from confirmation biases at multiple levels. At the top of the research pyramid sits the ‘Pharaoh’, Regius Professor Sir Simon Wessely KB, MA, BM BCh, MSc, MD, FRCP, FRCPsych, F Med Sci, FKC, Knight of the Realm, king-pin and originator of the Wessely School. The principal investigators (PIs) for the PACE Trial were Professors White, Chalder and Sharpe, the ‘Inner Circle’ of the Wessely School. Another Inner Circle member, Sir Mansel Aylward, then at the Department for Work and Pensions, was a funder of the trial. The PIs all have or had connections both to the Department for Work and Pensions and to insurance companies.

The investigators obtained close to £5,000,000 of tax payers’ money to run the PACE trial.

The objective of the trial was to demonstrate that two treatments based on the DBT, cognitive behavioural therapy (CBT) and graded exercise therapy (GET), help ME/CFS patients to recover. 

There was a zero chance the PACE researchers would fail to obtain the results they wanted. As the PACE ship left port, it went directly towards its destination. Only when it struck that unfortunate iceberg called “Null Result” did things begin to go seriously wrong.

Groupthink, Conflicts and Manipulation

The PACE trial team were operating within a closed system or groupthink in which they ‘know’ their theory is correct. With every twist and turn, no matter what the actual data show, the investigators are able to confirm their theory. The process is well-known in Psychology. It is a self-indulgent processes of subjective validation and confirmation bias.  Groupthink occurs when a group makes faulty decisions because group pressures lead to a deterioration of “mental efficiency, reality testing, and moral judgment” (Janis, 1972). Given this context, we can see reasons to question the investigators’ impartiality with many potential conflicts of interest (Lubet, 2017). Furthermore, critical analysis suggests that the PACE investigators involved themselves in manipulating protocols midway through the trial, selecting confirming data and omitting disconfirming data, and publishing biased reports of findings which created a catalogue of errors.

‘Travesty of Science’

The PACE Trial has been termed a ‘travesty of science’ while sufferers of ME/CFS continue to be offered unhelpful or harmful treatments and are basically being told to ‘pull themselves together’. One commentator has asserted that the situation for ME patients in the UK is: “The 3 Ts – Travesty of Science; Tragedy for Patients and Tantamount to Fraud” (Professor Malcolm Hooper, quoted by Williams, 2017). Serious errors in the design, the protocol and procedures of the PACE Trial are evident. The catalogue of errors is summarised below. The PACE Trial was loaded towards finding significant treatment effects.

When Disaster Strikes

The claimed benefits of GET and CBT for patient recovery are entirely spurious. The explanation lies in a sequence of serious errors in the design, the changed protocol and procedures of the PACE Trial. The investigators neglected or bypassed accepted scientific procedures for a RCT, as follows:

ErrorCategory of errorDescription of error
1Ethical issue: Applying for ethical approval and funding for a long-term trial when the PIs knew already knew CBT effects on ME/CFS were short-lived.On 3rd November 2000, Sharpe confirmed: “There is a tendency for the difference between those receiving CBT and those receiving the comparison treatment to diminish with time due to a tendency to relapse in the former” (www.cfs.inform/dk). Wessely stated in 2001 that CBT is “not remotely curative” and that: “These interventions are not the answer to CFS” (Editorial: JAMA 19th September 2001:286:11) (Williams, 2016).
2Ethical issue: Failure to declare conflicts of interest to Joint Trial Steering Committee.Undeclared conflicts of interest by the three PIs in the Minutes of the Joint Trial Steering Committee and Data Monitoring Committee held on 27th September 2004.
3Ethical issue: Failure to obtain fully informed consent after non-disclosure of conflicts of interest.Failing to declare their vested financial interests to PACE participants, in particular, that they worked for the PHI industry, advising claims handlers that no payments should be made until applicants had undergone CBT and GET.
4Use of their own discredited “Oxford” criteria for entry to the trial.Patients with ME would have been screened out of the PACE Trial even though ME/CFS has been classified by the WHO as a neurological disease since 1969 (ICD-10 G93.3).
5Inadequate outcome measures.Using only subjective outcome measures.The original protocol included the collection of actigraphy data as an objective outcome measure. However, after the Trial started, the decision was taken that no post-intervention actigraphy data should be obtained.
6Changing the primary outcomes of the trial after receiving the raw data.Altering outcome measures mid-trial in a manner which gave improved outcomes.
7Changing entry criteria midway through the trial.Altering the inclusion criteria for trial entry after the main outcome measures were lowered so that some participants (13%) met recovery criteria at the trial entry point.
8The statistical analysis plan was published two years after selective results had been published.The Re-definition of “recovery” was not specified in the statistical analysis plan.
9Inadequate controlSending participants newsletters promoting one treatment arm over another, thus contaminating the trial.
10Inadequate controlLack of comparable placebo/control groups with inexperienced occupational therapists providing a control treatment and experienced therapists provided CBT.
11Inadequate controlRepeatedly informing participants in the GET and CBT groups that the therapies could help them get better.
12Inadequate controlGiving patients in the CBT and GET arms having more sessions than in the control group.
13Inadequate controlAllowing therapists from different arms to communicate with each other about how patients were doing.
14Lack of transparencyBlocking release of the raw data for five years preventing independent analysis by external experts.

Credit where credit is due

A significant amount of investigation about the PACE trial was carried out in 2015 by David Tuller.

Please see:

Tuller D (2015) TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study. http://www.virology.ws/2015/10/21/trial-by-error-i/

Tuller D (2015) TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue Syndrome Study (second installment). http://www.virology.ws/2015/10/22/trial-by-error-ii/

Tuller D (2015) TRIAL BY ERROR: The Troubling Case of the PACE Chronic Fatigue (final installment) http://www.virology.ws/2015/10/23/trial-by-error-iii/

Tuller (2016) http://www.virology.ws/2016/02/01/trial-by-error-continued-a-few-words-about-harassment/

Other significant pieces of exposure were:

Goldin R. PACE: The research that sparked a patient rebellion and challenged medicine. www.stats.org/pace-research-sparked-patient-rebellion-challenged-medicine

This paper by Dr Mark Vink was described in a letter to the Editor of Lancet from Professor Malcolm Hooper as “The final coup de grace“:

The PACE Trial Invalidates the Use of Cognitive Behavioral and Graded Exercise Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review. J Neurol Neurobiol 2(3).

PACE-Gate: the Cover-Up

Blocking release of the raw data for five years and preventing independent analysis by external experts was tantamount to a cover-up of the true findings. An editorial by Keith Geraghty (2016) was entitled ‘PACE-Gate’. ME/CFS patient associations were rightly suspicious of the recovery claims concerning the GET arm of the trial because of their own experiences of intense fatigue after ordinary levels of activity which were inconsistent with the recovery claims of the PACE Trial reports. For many sufferers, even moderate exercise results in long ‘wipe-outs’ in which they are almost immobilized by muscle weakness and joint pain. In the US, post-exertional relapse has been recognized as the defining criterion of the illness by the Centers for Disease Control, the National Institutes of Health and the Institute of Medicine. For the PACE investigators, however, the announced recovery results validated their conviction that psychotherapy and exercise provided the key to reversing ME/CFS.

Alem Matthees Obtains Data Release

When Alem Matthees, a ME/CFS patient, sought the original data under the Freedom of Information Act and a British Freedom of Information tribunal ordered the PACE team to disclose their raw data, some of the data were re-analysed according to the original protocols. The legal costs of the tribunal at which QMUL were forced to release the data, against their strenuous objections, was over £245,000. The re-analysis of the PACE Trial data revealed that the so-called “recovery” under CBT and GET all but disappeared (Carolyn Wilshire, Tom Kindlon, Alem Matthees and Simon McGrath, 2016). The recovery rate for CBT fell to seven percent and the rate for GET fell to four percent, which were statistically indistinguishable from the three percent rate for the untreated controls. 

Graded exercise and CBT are still being routinely prescribed for ME/CFS in the UK despite patient reports that the treatments can cause intolerable pain and relapse. The analysis of the PACE Trial by independent critics has revealed a catalogue of errors and provides an object lesson in how not to conduct a scientific trial. The trial can be useful to instructors in research design and methodology for that purpose.

Following the re-analyses of the PACE Trial, the DBT is dead in the water. There is an urgent need for new theoretical approaches and scientifically-based treatments for ME/CFS patients. Meanwhile, there is repair work to be done to rebuild patient trust in the medical profession.

The Final Sinking

Caroline Wilshire, Tom Kindlon, Alem Matthees and Simon McGrath asked a very simple question:

Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy?

These authors gave a critical commentary and preliminary re-analysis of the PACE
trial. I quote their Abstract:

BACKGROUND: Publications from the PACE trial reported that 22%
of chronic fatigue syndrome patients recovered following graded
exercise therapy (GET), and 22% following a specialised form of
CBT. Only 7% recovered in a control, no-therapy group. These
figures were based on a definition of recovery that differed
markedly from that specified in the trial protocol.
PURPOSE: To evaluate whether these recovery claims are justified
by the evidence.
METHODS: Drawing on relevant normative data and other research,
we critically examine the researchers’ definition of recovery, and
whether the late changes they made to this definition were
justified. Finally, we calculate recovery rates based on the original
protocol-specified definition.
RESULTS: None of the changes made to PACE recovery criteria were
adequately justified. Further, the final definition was so lax that on
some criteria, it was possible to score below the level required for
trial entry, yet still be counted as ‘recovered’. When recovery was
defined according to the original protocol, recovery rates in the
GET and CBT groups were low and not significantly higher than in
the control group (4%, 7% and 3%, respectively).
CONCLUSIONS: The claim that patients can recover as a result of
CBT and GET is not justified by the data, and is highly misleading

Implications

  1. The PACE trial is/was/and always will be an unmitigated disaster. I use it in my textbook as an example of how not to do a trial.
  2. The authors and sponsors have done a disservice to science and to patients that will be hard to forget.
  3. An apology is the least that the principal investigators can do to make amends for this dreadful piece of pseudo-science.
  4. The universities involved should return the public funds that were wasted on the PACE trial project.
  5. A government enquiry is necessary to investigate the full facts in relation to the connections between the investigators, the insurance industry and the UK Department of Work and Pensions.

Note: This post is dedicated to Alem Matthees who has dedicated his life to the search for the truth about ME/CFS and was responsible for obtaining the release of the PACE trial data.

Reference:

David F Marks et al. (2020) Health Psychology. Theory, Research & Practice (6th ed.) SAGE Publications Ltd.

ME/CFS and the Wessely School

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In a series of posts I review the Wessely School’s influence on science, treatment and – most importantly – ME/CFS patient experience. In previous posts I outlined here the likely biological basis of ME/CFS and here treatment harms to patients. This post introduces the Wessely School’s approach to ME/CFS and medically unexplained symptoms.

What is ME/CFS?

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating
multisystemic disease of unknown aetiology, affecting thousands of individuals worldwide. The severity of symptoms can range from mild to severe with incidence peaks between age 10-19 years and 30-39 years.  Women are more often affected than men in a 3:1 ratio. ME/CFS has been described as an “incurable, invisible contested and unsupported illness” (Farrell Delaney, 2020).  The report by the Institute of Medicine (IOM) of the Academy of Sciences in the USA in 2015 concluded that ME/CFS is a physiological/medical, not a psychiatric illness (Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2015; Clayton, 2015). The International Consensus Criteria (Carruthers et al., 2011), the Centers for Disease Control and Prevention (2018), the ICD-10, and the ICD-11 (World Health Organisation, 2018), all classify ME/CFS as a neurological disease. 

In spite of evidence that the disease is associated with marked biological changes (Loebel et al., 2016, Schreiner et al., 2020; Sotzny et al., 2018; van Campen et al., 2020) and what appears to be a breakdown in homeostasis (Marks, 2021), the disease is often perceived by doctors and nurses as having a psychological or psychosomatic origin that is ‘all in the head’ (Åsbring & Närvänen, 2002; Dickson et al., 2007; Ware, 1992). This ‘all in the head’ perception causes stigmatization as an extra burden for patients with ME/CFS.  

Reorientation necessary

Paediatrician Ola Didrik Saugstad has stated: “A reorientation of the understanding and attitude to ME patients occurs worldwide. ME patients, especially the worse cases, suffer enormously. Among them, the paediatric patients are most vulnerable, representing a special challenge due to the occurrence in the midst of somatic growth and emotional development. We are waiting for a biomarker of this disease, and some are in the pipeline. And even more, we are hoping for an effective treatment. Still, it is already now time for the medical profession as well as the whole society to repent, as these patients have previously often not been treated with the respect and care they need and deserve” (Saugstad, 2020).

In addition to the stigma and stress burdens, the most used therapies for pwME/CFS based on the psychosocial model have caused significant harms to patients that are well documented in the literature.

Owing to the absence of an established biomarker, current diagnostic methods proceed by a process of eliminating other diseases with similar symptoms and there is no universally agreed or empirically derived definition of ME/CFS. The illness was first described in the mid-1980s when almost nothing was known about its underlying biology. Some clinicians explained to patients that “there is nothing wrong.”

Post-exertional malaise (PEM) is a cardinal symptom of ME/CFS reported by many, but not all, patients (Jason, Evans, So, Scott & Brown, 2015; VanNess, Snell & Stevens, 2007; McGregor, Armstrong, Lewis & Gooley, 2019).). In the International Classificatory System, PEM is a mandatory feature of the condition (Carruthers et al., 2003, 2011). Another commonly reported feature of the illness is its tendency to wax and wane (Friedman,  Bateman, Bested, & Nahle, 2019;  Morris, Anderson, Galecki, Berk & Maes, 2013; Morris & Maes, 2014). The onset and duration of ME/CFS have been debated with some researchers suggesting a sudden onset and others a gradual onset. An interview study revealed descriptions of ME/CFS onset experiences that were both varied and complex  indicating that onset can be sudden or gradual in different cases (Evans & Jason, 2018). 

For more than thirty years

a group of psychiatrists and psychologists at King’s College London and the Institute of Psychiatry together with a large group of collaborators has advanced a psychosomatic approach to ME/CFS. This group is given the sobriquet ‘Wessely School’ in honour of its leading representative, Professor Sir Simon Wessely. Simon Wessely has been the UK’s leading authority in establishing healthcare for patients with ME/CFS and MUS. According to the Wessely School, ME/CFS is neither a neurological nor an immunological condition but a psychosomatic condition, a functional illness with a primarily psychological origin.  For the Wessely School, ME/CFS belongs in a spectrum of medically unexplained symptoms (MUS) including irritable bowel syndrome, non-ulcer dyspepsia, premenstrual syndrome, chronic pelvic pain, fibromyalgia, atypical or non-cardiac chest pain, hyperventilation syndrome, tension headache, atypical facial pain, globus syndrome and multiple chemical sensitivity (Wessely, Nimnuan & Sharpe, 1999). Early in the piece these authors opined that “the existing definitions of these syndromes in terms of specific symptoms is of limited value”.

The psychologists and psychiatrists within the Wessely School favour the

Cognitive Behaviour Therapy (CBT) Model

of emotional distress as proposed by Aaron T Beck (1976). The model distinguishes between developmental predispositions and precipitants of distress, and perpetuating cognitive, behavioural, affective and physiological factors, the  so-called  “three Ps”: predisposing, precipitating and perpetuating factors (Beck, 1976). This approach is not dissimilar to Hans Eysenck’s view that personality and feelings of hopelessness and helplessness are causal determinants of diseases such as cancer and coronary heart disease (Eysenck, 1991, Figure 1).

In line with Beck’s and Eysenck’s approach, the Wessely School has promoted what it has called a “broadly conceptualized cognitive behavioural model of MUS suggest(ing) a novel and plausible mechanism of symptom generation.” In a nutshell, fears and beliefs about the harmful effects of activity are related to poorer outcomes in ME/CFS (Deary, Chalder & Sharpe, 2007).

The school holds the hypothesis that the ‘three Ps’ inform behaviour such as activity avoidance and the belief that the illness has an organic basis, which, in turn, are said to affect the patient’s physiology and symptoms, providing a vicious circle of symptom maintenance irrespective of symptom type. 

Some of the main influencers on the school have been Aaron T Beck, George Engel, Hans J Eysenck and Isaac M Marks. Eysenck’s theory assigns to cortisol and immune deficiency a mediating role between feelings of hopelessness and helplessness and development of the disease (see Figure 1).

Eysenck:  Psychosocial -> Biological -> Disease

Figure 1. Hans Eysenck’s theory of personality and stress, dysfunctional feelings, as the causes of cancer. From Eysenck (1991).

Wessely’s theory attributes causal status to fear, behaviour and de-conditioning (Figure 2). Eysenck’s theory and Wessely’s theory share a strongly biopsychosocial orientation but with a difference in the sequence of the three key elements:

Wessely:  Biological -> Psychosocial -> Disease

Figure 2.  The Wessely School’s theory of the aetiology of CFS. From  Harvey and Wessely, 2009.

Treatment of ME/CFS in the Wessely School’s approach focuses on the alleged ‘self-perpetuating cycle’ of inactivity that is assumed to disrupt the “self-maintaining interlock of cognitive, behavioural and physiological responses hypothesised to perpetuate the symptoms” (Deary et al. 2007, pp. 2-3; Harvey & Wessely, 2009; Figure 2).

The role of doctors in MUS is said to be similar to that of “parents of sick children. Both can reinforce unhelpful illness behaviour and symptom interpretations” (Deary et al., 2007, p. 7). 

A group of investigators in Nijmegen, The Netherlands, holds a similar hypothesis that emphasizes the role of physical activity in attempting to correct the so-called ‘vicious circle’ of ME/CFS (Vercoulen et al., 1998; Wiborg, Knoop, Stulemeijer, Prins & Bleijenberg, 2010).

Influencers of the Wessely School

There have been several major influencers on the School including:

Aaron T Beck: the ‘Father’ of both cognitive therapy and cognitive behaviour therapy.

George L Engel: founder of the biopsychosocial model.

Hans J Eysenck: a leading theorist in personality theory and behaviour therapy. However, Eysenck’s publications on smoking, cancer and CHD were recently considered ‘unsafe’ in an enquiry within King’s College London.

Isaac M Marks: leading South African/UK psychiatrist specialising in anxietyphobicobsessive-compulsive and sexual disorders and behavioral psychotherapy.

Inner Circle

Key members of an ‘inner circle’ are also shown in the illustration:

Trudie Chalder: Professor of Cognitive Behavioural Psychotherapy, King’s College London. Chalder has co-authored multiple publications on ME/CFS and MUS with Professor Wessely and she was one of the co-principal investigators of the PACE trial.

Mansell Aylward: Director of the Centre for Psychosocial Research, Occupational and Physician Health, Cardiff University. From 1996 to April 2005 Aylward was Chief Medical Adviser, Medical Director and Chief Scientist of the UK Department for Work and Pensions, co-funder of the PACE trial.

Peter D White: retired Professor of Psychological Medicine at Queen Mary University of London, United Kingdom, one of the co-principal investigators of the PACE trial.

Michael Sharpe: Professor of Psychological Medicine at the University of Oxford (previously at the University of Edinburgh) and one of the co-principal investigators of the PACE trial.

A larger ‘outer ring’ of collaborators work at King’s College London and at many other institutions all over the world.

The Wessely School’s Contribution

The Wessely School’s influence on the treatment of patients with ME/CFS has been huge. Some main influencers and contributors are listed in the table together with statements and publications reflecting the approach.

INFLUENCERS AND CONTRIBUTORSPUBLICATIONS AND PERSONNEL
Epictetus“People are not disturbed by things, but by the views they take of them”.
James AlexanderThought control in everyday life. (1928). Funk & Wagnalls, New York.
Aaron T Beck Depression: Causes and treatment. (1967). University of Pennsylvania Press, Philadelphia.
Albert EllisA cognitive approach to behaviour therapy. (1969). Internat. J Psychother, 8, 896-900.
Joseph Wolpe  and Arnold LazarusBehavior therapy techniques: A guide to the treatment of neuroses. (1966).Pergamon Press.
Hans J EysenckPersonality, cancer and cardiovascular disease: A causal analysis (1985). Personality and individual differences, 6(5), 535-556.
Isaac M MarksFears, phobias, and rituals: Panic, anxiety, and their disorders. (1987).Oxford University Press.
George L Engel  The need for a new medical model: A challenge for biomedicine (1977). Science, 196, 129–136.
Harold Leventhal, D. Meyer and  D. Nerenz (1980).  The common-sense model of illness danger. In: Rachman, S., editors. Medical Psychology, Vol. 2. New York: Pergamon, pp. 7–30.
Core Team Members at King’s College LondonT Chalder, J Chilcot, P McCrone, K Goldsmith,  M. Hotopf,  R Moss-Morris,  J Weinman, S Wessely
External contributors  M. Alyward (UnumProvident Centre, Cardiff), C. Bass (Oxford), G. Bleijenberg (Nijmegen), S. Borgo (Rome), K. Brurburg (Norwegian Institute of Public Health), C. Burton (Sheffield), D. L. Cox (Cumbria), E. Crawley (Bristol),  V. Deary (Newcastle), L. Dennison (Southampton), R. Horne (UCL), A.L. Johnson (MRC Clinical Trials Unit, London), H. Knoop (Nijmegen), M. Loades (Bath), D.Oakley (UCL), K. Petrie (Auckland), M. Sharpe (Oxford), L.  Sibelia (Rome), P. D. White (Queen Mary University of London) 

In later posts I present the scientific evidence on the Wessely School’s approach to ME/CFS and MUS.

Watch this space!

Special issue on the PACE Trial

We are proud that this issue marks a special contribution by the Journal of Health Psychology to the literature concerning interventions to manage adaptation to chronic health problems. The PACE Trial debate reveals deeply embedded differences between critics and investigators. It reveals an unwillingness of the co-principal investigators of the PACE trial to engage in authentic discussion and debate. It leads one to question the wisdom of such a large investment from the public purse (£5million) on what is a textbook example of a poorly done trial.

The Journal of Health Psychology received a submission in the form of a critical review of one of the largest psychotherapy trials ever done, the PACE Trial. PACE was a trial of therapies for patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), a trial that has been associated with a great deal of controversy (Geraghty, 2016). Following publication of the critical paper by Keith Geraghty (2016), the PACE Trial investigators responded with an Open Peer Commentary paper (White et al., 2017). The review and response were sent to more than 40 experts on both sides of the debate for commentaries.

The resulting collection is rich and varied in the perspectives it offers from a neglected point of view. Many of the commentators should be applauded for their courage, resilience and ‘insider’ understanding of experience with ME/CFS.

The Editorial Board wants to go on record that the PACE Trial investigators and their supporters were given numerous opportunities to participate, even extending the possibility of appeals and re-reviews when they would not normally be offered. That they failed to respond appropriately is disappointing.

Commentaries were invited from an equal number of individuals on both sides of the debate (about 20 from each side of the debate). Many more submissions arrived from the PACE Trial critics than from the pro-PACE side of the debate. All submissions were peer reviewed and judged on merit.

The PACE Trial investigators’ defence of the trial was in a template format that failed to engage with critics. Before submitting their reply, Professors Peter White, Trudie Chalder and Michael Sharpe wrote to me as co-principal investigators of the PACE trial to seek a retraction of sections of Geraghty’s paper, a declaration of conflicts of interest (COI) by Keith Geraghty on the grounds that he suffers from ME/CFS, and publication of their response without peer review (White et al., 4 November 2016, email to David F Marks). All three requests were refused.

On the question of COI, the PACE authors themselves appear to hold strong allegiances to cognitive behavioural therapy (CBT) and graded exercise therapy (GET) – treatments they developed for ME/CFS. Stark COI have been exposed by the commentaries including the PACE authors themselves who hold a double role as advisers to the UK Government Department of Work and Pensions (DWP), a sponsor of PACE, while at the same time working as advisers to large insurance companies who have gone on record about the potential financial losses from ME/CFS being deemed a long-term physical illness. In a further twist to the debate, undeclared COI of Petrie and Weinman (2017) were alleged (Lubet, 2017). Professors Weinman and Petrie adamantly deny that their work as advisers to Atlantis Healthcare represents a COI.

After the online publication of several critical Commentaries, Professors White, Sharpe, Chalder and 16 co-authors were offered a further opportunity to respond to their critics in the round but they chose not to do so.

After peer review, authors were invited to revise their manuscripts in response to reviewer feedback and many made multiple drafts. The outcome is a set of robust papers that should stand the test of time and offer significant new light on what went wrong with the PACE Trial that has been of such high significance for the nature of treatment protocols. It is disappointing that what has been the more dominant other side refused to participate.

Unfortunately, across the pro-PACE group of authors there was a consistent pattern of resistance to the debate. After receiving critical reviews, the pro-PACE authors chose to make only cosmetic changes or not to revise their manuscripts in any way whatsoever. They appeared unwilling to enter into the spirit of scientific debate. They acted with a sense of entitlement not to have to respond to criticism. Two pro-PACE authors even showed disdain for ME/CFS patients, stating: We have no wish to get into debates with patients. In another instance, three pro-PACE authors attempted to subvert the journal’s policy on COI by recommending reviewers who were strongly conflicted, forcing rejection of their paper.

The dearth of pro-PACE manuscripts to start off with (five submissions), the poor quality, the intransigence of authors to revise and the unavoidable rejection of three pro-PACE manuscripts led to an imbalance in papers between the two sides. However, this editor was loathe to compromise standards by publishing unsound pieces in spite of the pressure to go ahead and publish from people who should know better.

We are proud that this issue marks a special contribution by the Journal of Health Psychology to the literature concerning interventions to manage adaptation to chronic health problems. The PACE Trial debate reveals deeply embedded differences between critics and investigators. It also reveals an unwillingness of the co-principal investigators of the PACE trial to engage in discussion and debate. It leads one to question the wisdom of such a large investment from the public purse (£5 million) on what is a textbook example of a poorly done trial.

ME/CFS research has been poorly served by the PACE Trial and a fresh new approach to treatment is clearly warranted. On the basis of this Special Issue, readers can make up their own minds about the scientific merits and demerits of the PACE Trial. It is to be hoped that the debate will provide a more rational basis for evidence-based improvements to the care pathway for hundreds of thousands of patients.

References

Geraghty, KJ (2016‘PACE-Gate’: When clinical trial evidence meets open data access. Journal of Health Psychology 22(9): 11061112Google ScholarSAGE JournalsISI
Lubet, S (2017Defense of the PACE trial is based on argumentation fallacies. Journal of Health Psychology 22(9): 12011205Google ScholarSAGE JournalsISI
Petrie, K, Weinman, J (2017The PACE trial: It’s time to broaden perceptions and move on. Journal of Health Psychology 22(9): 11981200Google ScholarSAGE JournalsISI
White, PD, Chalder, T, Sharpe, M. (2017Response to the editorial by Dr Geraghty. Journal of Health Psychology 22(9): 11131117Google ScholarSAGE JournalsISI

The Editorial has been abridged and the photograph of Dr. Keith Geraghty added.

The PACE Trial: A Catalogue of Errors

What was the PACE Trial?

Rarely in the history of clinical medicine have doctors and patients been placed so bitterly at loggerheads. The dispute had been a long time coming. Thirty years ago, a few psychiatrists and psychologists offered a hypothesis based on a Psychological Theory in which ME/CFS is constructed as a psychosocial illness. According to their theory, ME/CFS patients have “dysfunctional beliefs” that their symptoms are caused by an organic disease. The ‘Dysfunctional Belief Theory’ (DBT) assumes that no underlying pathology is causing the symptoms; patients are being ‘hypervigilant to normal bodily sensations‘ (Wessely et al., 1989; Wessely et al., 1991).

The Psychological Theory assumes that the physical symptoms of ME/CFS are the result of ‘deconditioning’ or ‘dysregulation’ caused by sedentary behaviour, accompanied by disrupted sleep cycles and stress. Counteracting deconditioning involves normalising sleep cycles, reducing anxiety levels and increasing physical exertion. To put it bluntly, the DBT asserts that ME/CFS is ‘all in the mind’.  Small wonder that patient groups have been expressing anger and resentment in their droves.

Top-Down Research

‘Top-down research’ uses a hierarchy of personnel, duties and skill-sets. The person at the top sets the agenda and the underlings do the work. The structure is a bit like the social hierarchy of ancient Egypt. Unless carefully managed, this top-down approach risks creating a self-fulfilling prophecy from confirmation biases at multiple levels. At the top of the research pyramid sits the ‘Pharaoh’, Regius Professor Sir Simon Wessely KB, MA, BM BCh, MSc, MD, FRCP, FRCPsych, F Med Sci, FKC, Knight of the Realm, President of the Royal College of Medicine, and originator of the DBT.  The principal investigators (PIs) for the PACE Trial, Professors White, Chalder and Sharpe, are themselves advocates of the DBT.  The PIs all have or had connections both to the Department of Work and Pensions and to insurance companies. The objective of the PACE Trial was to demonstrate that two treatments based on the DBT, cognitive behavioural therapy (CBT) and graded exercise therapy (GET), help ME/CFS patients to recover. There was zero chance the PACE researchers would fail to obtain the results they wanted. 

Groupthink, Conflicts and Manipulation

The PACE Trial team were operating within a closed system or groupthink in which they ‘know’ their theory is correct. With every twist and turn, no matter what the actual data show, the investigators are able to confirm their theory. The process is well-known in Psychology. It is a self-indulgent processes of subjective validation and confirmation bias.  Groupthink occurs when a group makes faulty decisions because group pressures lead to a deterioration of “mental efficiency, reality testing, and moral judgment” (Janis, 1972). Given this context, we can see reasons to question the investigators’ impartiality with many potential conflicts of interest (Lubet, 2017). Furthermore, critical analysis suggests that the PACE investigators involved themselves in manipulating protocols midway through the trial, selecting confirming data and omitting disconfirming data, and publishing biased reports of findings which created a catalogue of errors.

‘Travesty of Science’

The PACE Trial has been termed a ‘travesty of science’ while sufferers of ME/CFS continue to be offered unhelpful or harmful treatments and are basically being told to ‘pull themselves together’. One commentator has asserted that the situation for ME patients in the UK is: The 3 Ts – Travesty of Science; Tragedy for Patients and Tantamount to Fraud” (Professor Malcolm Hooper, quoted by Williams, 2017). Serious errors in the design, the protocol and procedures of the PACE Trial are evident. The catalogue of errors is summarised below. The PACE Trial was loaded towards finding significant treatment effects.

A Catalogue of Errors

The claimed benefits of GET and CBT for patient recovery are entirely spurious. The explanation lies in a sequence of serious errors in the design, the changed protocol and procedures of the PACE Trial. The investigators neglected or bypassed accepted scientific procedures for a RCT, as follows:

Error Category of error Description of error
1Ethical issue: Applying for ethical approval and funding for a long-term trial when the PIs knew already knew CBT effects on ME/CFS were short-lived. On 3rd November 2000, Sharpe confirmed: “There is a tendency for the difference between those receiving CBT and those receiving the comparison treatment to diminish with time due to a tendency to relapse in the former” (www.cfs.inform/dk). Wessely stated in 2001 that CBT is “not remotely curative” and that: “These interventions are not the answer to CFS” (Editorial: JAMA 19th September 2001:286:11) (Williams, 2016).
2Ethical issue: Failure to declare conflicts of interest to Joint Trial Steering Committee.Undeclared conflicts of interest by the three PIs in the Minutes of the Joint Trial Steering Committee and Data Monitoring Committee held on 27th September 2004.
3Ethical issue: Failure to obtain fully informed consent after non-disclosure of conflicts of interest.Failing to declare their vested financial interests to PACE participants, in particular, that they worked for the PHI industry, advising claims handlers that no payments should be made until applicants had undergone CBT and GET.
4Use of their own discredited “Oxford” criteria for entry to the trial.Patients with ME would have been screened out of the PACE Trial even though ME/CFS has been classified by the WHO as a neurological disease since 1969 (ICD-10 G93.3).
5Inadequate outcome measures.Using only subjective outcome measures.The original protocol included the collection of actigraphy data as an objective outcome measure. However, after the Trial started, the decision was taken that no post-intervention actigraphy data should be obtained.
6Changing the primary outcomes of the trial after receiving the raw data. Altering outcome measures mid-trial in a manner which gave improved outcomes.
7Changing entry criteria midway through the trial. Altering the inclusion criteria for trial entry after the main outcome measures were lowered so that some participants (13%) met recovery criteria at the trial entry point.
8The statistical analysis plan was published two years after selective results had been published. The Re-definition of “recovery” was not specified in the statistical analysis plan.
9Inadequate control Sending participants newsletters promoting one treatment arm over another, thus contaminating the trial.
10Inadequate controlLack of comparable placebo/control groups with inexperienced occupational therapists providing a control treatment and experienced therapists provided CBT.
11Inadequate controlRepeatedly informing participants in the GET and CBT groups that the therapies could help them get better.
12Inadequate control Giving patients in the CBT and GET arms having more sessions than in the control group.
13Inadequate controlAllowing therapists from different arms to communicate with each other about how patients were doing.

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Lack of transparency

Blocking release of the raw data for five years preventing independent analysis by external experts.

Cover-Up

Blocking release of the raw data for five years and preventing independent analysis by external experts was tantamount to a cover-up of the true findings. An editorial by Keith Geraghty (2016) was entitled ‘PACE-Gate’. ME/CFS patient associations were rightly suspicious of the recovery claims concerning the GET arm of the trial because of their own experiences of intense fatigue after ordinary levels of activity which were inconsistent with the recovery claims of the PACE Trial reports. For many sufferers, even moderate exercise results in long ‘wipe-outs’ in which they are almost immobilized by muscle weakness and joint pain. In the US, post-exertional relapse has been recognized as the defining criterion of the illness by the Centers for Disease Control, the National Institutes of Health and the Institute of Medicine. For the PACE investigators, however, the announced recovery results validated their conviction that psychotherapy and exercise provided the key to reversing ME/CFS.

Alem Matthees Obtains Data Release

When Alem Matthees, a ME/CFS patient, sought the original data under the Freedom of Information Act and a British Freedom of Information tribunal ordered the PACE team to disclose their raw data, some of the data were re-analysed according to the original protocols. The legal costs of the tribunal at which QMUL were forced to release the data, against their strenuous objections, was over £245,000. The re-analysis of the PACE Trial data revealed that the so-called “recovery” under CBT and GET all but disappeared (Carolyn Wilshire, Tom Kindlon, Alem Matthees and Simon McGrath, 2016). The recovery rate for CBT fell to seven percent and the rate for GET fell to four percent, which were statistically indistinguishable from the three percent rate for the untreated controls. Graded exercise and CBT are still being routinely prescribed for ME/CFS in the UK despite patient reports that the treatments can cause intolerable pain and relapse. The analysis of the PACE Trial by independent critics has revealed a catalogue of errors and provides an object lesson in how not to conduct a scientific trial. The trial can be useful to instructors in research design and methodology for that purpose.

Following the re-analyses of the PACE Trial, the DBT is dead in the water. There is an urgent need for new theoretical approaches and scientifically-based treatments for ME/CFS patients. Meanwhile, there is repair work to be done to rebuild patient trust in the medical profession after this misplaced attempt to apply the Psychological Theory to the unexplained syndrome of ME/CFS. The envelope theory of Jason et al. (2009) proposes that people with ME/CFS need to balance their perceived and expended energy levels and provides one way forward, pending further research.

Ultimately, patients, doctors and psychologists are waiting for an organic account of ME/CFS competent to explain the symptoms and to open the door to effective treatments. Patients have a right to nothing less.

An extract from: David F Marks et al. (2018) Health Psychology. Theory, Research & Practice (5th ed.) SAGE Publications Ltd.