‘It’s time for an independent review of the PACE Trial methods and results’ | Dr Charles Shepherd, Journal of Health Psychology | 10 April 2017

April 10, 2017



Publication of different perspectives about the PACE Trial continues apace in the Journal of Health Psychology.


Yesterday, Dr Charles Shepherd, Hon. Medical Adviser to the ME Association appeared. Links to all the contributions published so far appear at the foot of this page.


The Journal agreed very quickly to the ME Association's suggestion that all these articles appear as Open Access.



PACE trial claims for recovery in myalgic encephalomyelitis/chronic fatigue syndrome – true or false? It’s time for an independent review of the methodology and results

Charles Bernard Shepherd


The PACE trial set out to discover whether cognitive behaviour therapy and graded exercise therapy are safe and effective forms of treatment for myalgic encephalomyelitis/chronic fatigue syndrome. It concluded that these interventions could even result in recovery. However, patient evidence has repeatedly found that cognitive behaviour therapy is ineffective and graded exercise therapy can make the condition worse. The PACE trial methodology has been heavily criticised by clinicians, academics and patients. A re-analysis of the data has cast serious doubts on the recovery rates being claimed. The trust of patients has been lost. The medical profession must start listening to people with myalgic encephalomyelitis/chronic fatigue syndrome if trust is going to be restored.


activity, behavioural medicine, chronic fatigue syndrome, cognitive behaviour therapy, dissatisfaction, efficacy, exercise, graded exercise therapy

Keith Geraghty’s (2016) editorial has identified and discussed most of the key reasons why both the PACE trial methodology and the results are not regarded as reliable. PACE – an acronym for Pacing, graded Activity, and Cognitive behaviour therapy, a randomised Evaluation – compared the effectiveness of four separate inteventions: specialist medical care (SMC) to SMC plus adaptive pacing therapy, cognitive behaviour therapy and graded exercise therapy in patients with myalgic encephalomyelitis/chronic fatigue syndrome. However, those involved in the PACE trial have responded by stating that these criticisms are based on misunderstandings and misrepresentations (White, 2017).

I would like to use this commentary to examine controversies surrounding how two of the PACE trial interventions – cognitive behaviour therapy (CBT) and graded exercise therapy (GET) – originated, why the PACE trial was bound to run into difficulties, and why the patient community is so at odds with the medical establishment over their promotion of CBT and GET.

As a physician who has spent much of the past 35 years helping patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS), I have a strong desire to find safe, acceptable and effective forms of treatment that are aimed at the underlying disease process – rather than just trying to relieve some of the key symptoms. The same position is taken by most ME/CFS patients.

However, uncertainties and disagreements among doctors and patients as to how we should name, define and diagnose this illness, what causes it and how it should be managed make this a very challenging task.

The failure to accept that ME/CFS is a very heterogeneous condition in both clinical presentations and underlying disease mechanisms has meant that the two ‘rehabilitative’ approaches to management – CBT and GET – which were assessed in the PACE trial have become the only forms of treatment for ME/CFS recommended by NICE (National Institute for Health and Clinical Excellence, 2011). At the same time, CBT and GET are consistently rejected by a substantial proportion of people with ME/CFS for being either ineffective (in the case of CBT) or harmful (in the case of GET).

This conflict over the management of ME/CFS largely dates back to a decision taken in the 1980s to rename and redefine what had previously been known as ME as CFS. By relaxing the diagnostic criteria, CFS brought in a much wider group of people who had some form of undiagnosed chronic fatigue that, in some cases, primarily involved psychological or psychiatric factors.

Based on a new and seriously flawed hypothesis that CFS was largely being maintained by abnormal illness beliefs and behaviours, along with inactivity and deconditioning, CBT and GET became the two main recommended forms of treatment in both the United Kingdom and the United States.

Prior to publication of the PACE trial results, a small number of clinical trials had supported the use of CBT and GET, almost all of which had been carried out by health professionals who promoted a psychosomatic model of causation and management. However, patient survey evidence, as collected by the ME Association (ME Association, 2015) along with most other patient surveys (Kindlon and Baldwin, 2015), told a very different story. The majority of people with ME/CFS consistently reported that CBT was ineffective. And around 50 per cent consistently reported that GET had made their condition worse.

The largest and most recent ME Association survey (ME Association, 2015) of patient evidence on the acceptability, efficacy and safety of CBT, GET and Pacing involved 1428 respondents. In this case, 73 per cent of respondents reported that CBT had no effect on their symptoms and 74 per cent reported that their symptoms were made worse by GET.

Surveys carried out by patient support groups have a number of limitations and these are listed in detail in section 6 of The ME Association survey results. In particular, it should be noted that people who belong to patient support groups, or use their websites, are going to produce a bias towards those who have been ill for a longer period of time and/or have a more severe form of illness. At the same time, those who have recovered, or have largely recovered, are less likely to belong to a support group or take part in surveys. So the respondents in these sort of surveys are not necessarily a representative sample of the whole ME/CFS population who have tried these therapies.

And while entry to this survey was on the basis of having a diagnosis of ME/CFS, we did not collect any clinical details or contact the health professional involved for confirmation.

So the PACE trial was essentially set up to provide robust evidence of both safety and efficacy for graded activity (i.e. GET), CBT and a modified version of pacing known as adaptive pacing. But PACE was a study that selected patients using a flawed diagnostic criteria (i.e. Oxford) and only assessed a limited number of subjective outcome measures focusing on fatigue and disability – a design that required strict vigilance in order to prevent the possibility of bias. Not surprisingly, PACE met with widespread criticism right from the very start.

The MEA argued that PACE was not taking account of the clinical heterogeneity of the illness and was ignoring the complex interaction between central (brain) and peripheral (muscle) factors in the causation of fatigue in ME/CFS.

With specific reference to graded exercise, muscle performance and the observation that exercise often makes symptoms worse, Brown et al. (2015) have used magnetic resonance spectroscopy to demonstrate that there are at least two muscle phenotypes involved in ME/CFS. This finding, along with other research evidence on abnormal exercise physiology (VanNess et al., 2003), that is not consistent with a deconditioning/inactivity model of causation, emphasises the need to fully characterise muscle phenotypes, as well as muscle biochemical abnormalities, before generically prescribing exercise as an effective intervention.

The MEA therefore argued that PACE was unlikely to tell us anything we did not already know from previous clinical trials involving CBT and GET. The charity also argued that PACE was a colossal waste of money that should be far better spent on much needed biomedical research – which the main funder of PACE, the Medical Research Council, had always been reluctant to do.

When the first PACE trial results were published (White et al., 2011), they once again failed to convince people with ME/CFS that CBT and GET were the most effective ways of managing everyone with mild or moderate ME/CFS.

But it was the follow-up paper on recovery in Psychological Medicine (White et al., 2013) – where it was claimed that CBT and GET led to ‘recovery’ in 22 per cent – that really intensified the debate into the methodology of the trial, the way recovery had been defined, and the manner in which the results were portrayed to clinicians, patients and the media. Key criticisms included the following:

Recovery figures were based on a definition of recovery that differed from that specified in the trial protocol. In fact, the final definition of recovery was so lax that on some criteria it was possible to score below the level required for entry to the trial, yet still be counted as ‘recovered’.

Participants were not even asked whether they had recovered in relation to normal aspects of daily living.

Information on overall receipt of state sickness or disability benefits failed to support a recovery – with the PACE trial cost analysis study (McCrone et al., 2012) reporting: ‘Receipt of benefits due to illness or disability increased slightly from baseline to follow-up’.

Information on return to some form of meaningful employment or education status was never sought. This was dismissed by the investigators as not being relevant.

Information on ability to mobilise failed to support a recovery. Overall results for all treatments relating to changes in the 6-minute walking test from baseline to 52 weeks did not represent a return to normal levels of activity. In fact, data for all the treatment groups at 52 weeks indicated that they were below the 402 m achieved by patients with class three heart failure. In addition, rejecting the use of electronic activity monitors meant no objective assessment of mobility was carried out.

The term ‘recovery’ implies a sustained return towards symptom-free health along with the ability to repeatedly and reliably participate in all aspects of normal life – employment, education, social activities and so on. Without this information, it was impossible to conclude that any of the patients in the PACE trial had usefully recovered.

Not surprisingly, criticism of the PACE trial continued and intensified. There was a debate in the House of Lords (UK House of Lords, 2013) and 36 academics and clinicians signed an open letter to The Lancet (ME Association, 2016) calling for an independent re-analysis of the data.

Several requests by academics, clinicians and patients asked for unpublished data to be made available so that it could be subjected to independent analysis. These demands were consistent with the growing acceptance by the scientific community that there should be far more transparency in clinical trials, including the sharing of data. The investigators refused to give way even when asked to do so by the Information Commissioner. Queen Mary University of London, which oversaw the trial, then spent almost £250,000 of public money on legal fees by taking the case to an appeal tribunal – which they lost.

When the unpublished PACE trial data was re-analysed by Wilshire et al. (2017), the authors found that if recovery was defined according to the original trial protocol, recovery rates in the CBT and GET groups were low and not significantly higher than in the control group (4%, 7% and 3%, respectively). The authors concluded, The claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.

I conclude with some observations on what we can learn from the mistakes of the PACE trial. Because if lessons are not learned, distrust of the medical and scientific community by the people with ME/CFS will only continue and intensify.

This is not an argument with psychiatry. Mental and physical illness are equally real and horrible. As with any long-term illness, some people with ME/CFS will develop comorbid depression and other mental health problems – where CBT can be of help alongside good quality general management. The argument here is with a flawed model of causation assuming efficacy for CBT and GET while taking no significant account of varying clinical presentations and disease pathways.

First, on behalf of all the journals that have so far published 16 papers from the trial, The Lancet must now set up an independent re-analysis of the PACE trial data, along with appropriate sensitivity analysis. This re-analysis should be carried out by well respected independent reviewers with expertise in statistics and study design. If any results are found to be significantly inaccurate or unreliable, the possibility of a retraction will have to be considered.

Second, if a drug treatment was found to be making a significant proportion of people worse, as is the case with patient evidence relating to the use of GET, the treatment would be withdrawn and would not form part of a NICE recommendation. As there is now both consistent and extensive patient evidence relating to the harmful effects of GET, the NICE guideline recommendation on GET must be reviewed as a matter of urgency. The generic prescribing of progressive and inflexible exercise programmes is not an acceptable form of treatment for people with ME/CFS.

Third, the enormous amount of public money spent by the Medical Research Council and Department of Work and Pensions on funding the PACE trial, along with legal costs met by Queen Mary University of London in appealing against the Freedom of Information requests, merits a formal inquiry, possibly at a parliamentary level.

Finally, there is a desperate need for clinical trials of activity management that examine the heterogeneity of ME/CFS, the fact that underlying disease processes involve both central and peripheral fatigue, and the consistent evidence from patients that inflexible or progressive exercise programmes aggravate symptoms in the majority of patients who come under the ME/CFS umbrella.


The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.


The author(s) received no financial support for the research, authorship and/or publication of this article.


Brown AE, Jones DE, Walker M, . (2015) Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome. PLoS ONE 2015; 10: e0122982.

Geraghty KJ (2016) PACE-gate: When clinical trial evidence meets open data access. Journal of Health Psychology. Epub ahead of print 1 November. DOI: 10.1177/1359105316675213.

Kindlon T, Baldwin A (2015) Response to: Reports of recovery in chronic fatigue syndrome may present less than meets the eye. Evidence Based Mental Health 18(2): e5.

McCrone P, Sharpe M, Chalder T, . (2012) Adaptive pacing, cognitive behaviour therapy, graded exercise, and specialist medical care for chronic fatigue syndrome: A cost-effectiveness analysis. PLoS ONE 7(8): e40808.

ME Association (2015) ME/CFS illness management survey results: ‘No decisions about me without me’. Available at:https://meassociation.org.uk/2015/05/23959/

ME Association (2016) Clamour grows for independent inquiry into PACE trial: Open letter to The Lancet republished. Available at: https://meassociation.org.uk/2016/02/clamour-grows-for-independent-inquiry-into-the-pace-trial-open-letter-to-the-lancet-republished-11-february-2016/

National Institute for Health and Clinical Excellence (2011) Review of clinical guideline (CG53) – Chronic fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): Diagnosis and management of chronic fatigue syndrome, myalgic encephalomyelitis (or encephalopathy) in adults and children. Available at: https://www.nice.org.uk/guidance/cg53/evidence/review-decision-2011-546258781

UK House of Lords (2013) PACE trial: Chronic fatigue syndrome/myalgic encephalomyelitis. Available at: http://www.publications.parliament.uk/pa/ld201213/ldhansrd/text/130206-gc0001.htm

VanNess JM, Snell CR, Strayer DR, . (2003) Subclassifying chronic fatigue syndrome through exercise testing. Medicine and Science in Sports and Exercise 35(6): 908–913.

White PD (2017) Response to editorial by Dr Geraghty. Journal of Health Psychology. Epub ahead of print 24 January. DOI: 10.1177/1359105316688953. Google Scholar

White PD, Goldsmith KA, Johnson AL, . (2011) PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): A randomized trial. The Lancet 377: 823–836.

White PD, Goldsmith K, Johnson AL, . (2013) Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 43(10): 2227–2235.

Wilshire C, Kindlon T, Matthees A, . (2017) Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior 5: 43–56.


  1. CFS patients have no reason to accept the PACE trial results: Response to Keith J Petrie and John Weinman – Susanna Agardy
  2. Cognitive behaviour therapy and objective assessments in chronic fatigue syndrome – Graham McPhee
  3. Further commentary on the PACE trial: Biased methods and unreliable outcomes – Keith J Geraghty
  4. Defense of the PACE trial is based on argumentation fallacies – Steven Lubet
  5. Bias, misleading information and lack of respect for alternative views have distorted perceptions of ME/CFS and its treatment – Ellen Goudsmit, Sandra Howes
  6. PACE-GATE: An alternative view on a study with a poor trial protocol – Bart Stouten
  7. PACE investigators’ response is misleading regarding patient survey results – Karen D Kirke
  8. PACE trial authors continue to ignore their own null effect – Mark Vink
  9. Once again, the PACE authors respond to concerns with empty answers – David Tuller
  10. PACE trial claims for recovery in ME/CFS – true or false? It’s time for an independent review of the methodology and results – Dr Charles Shepherd
  11. The PACE trial: It’s time to broaden perceptions and move on – Keith J Petrie, John Weinman
  12. PACE team response shows a disregard for the principles of science – Professor Jonathan Edwards
  13. The problem of bias in behavioural intervention studies: Lessons from the PACE trial – Carolyn Wilshire
  14. Do graded activity therapies cause harm in chronic fatigue syndrome? – Tom Kindlon
  15. Investigator bias and the PACE trial – Steven Lubet
  16. How have selection bias and disease misclassification undermined the validity of ME/CFS studies? – Dr Luis Nacul and colleagues at the UK ME/CFS Biobank
  17. The PACE trial missteps on pacing and patient selection (Professor Leonard A Jason)
  18. Response to the editorial by Dr Geraghty – Professor Peter D White, Professor Trudie Chalder, Professor Michael Sharpe and 16 others


3 thoughts on “‘It’s time for an independent review of the PACE Trial methods and results’ | Dr Charles Shepherd, Journal of Health Psychology | 10 April 2017”

  1. Yes, I agree, excellent article. Thanks.

    You suggest the Lancet set up an independent re-analysis of the PACE trial data. The Lancet has refused calls for a retraction following independent scientists providing re-analysis so far. How could we judge the independence of anyone appointed by the Lancet to do the re-analysis?

  2. There is another danger in the making now.

    The lead author of the IOM report on ME/CF states: ‘Although patients differ in their triggers and manifestations, the salient feature of this disorder is that any kind of exertion—physical, cognitive, emotional—can adversely affect these patients in many aspects of their biological function and in their lives, frequently severely and often for a prolonged period.’

    The ‘salient feature’ of this disease is that ‘any kind of exertion’. can ‘adversely affrect’ (do harm) ‘in many aspects of their biological function’. (biological damage) ‘frequently severely’ and often for a prolonged period.’

    Exertion, of any kind, can do multisystem, severe, longlasting biological damage.

    There can be no clearer statement of the potential damage inflicted by GET, which corresponds to patient experience.

    This isn’t ‘the complaints of a small but vociferous group of sociopathic patients’, as is claimed by Wessely and his colleagues.

    This is the conclusion of a panel assembled by the US NIH specifically for the purpose of examining all the research evidence, the ‘grey’ literature, and patient accounts.

    This conclusion is deserving of scientific and academic respect, and removes psychiatry and psychiatrists completely out of the picture.

    Of course they are not happy about this,nor about the reanalysis of the PACE data, or about the increasing accounts of biomedical research coming from the US and elsewhere, which Esther Crawley dismissed, on the Victoria Derbyshire show, as unwelcome distractions.

    However, Simon Wessely is a very resourceful and powerful person, ranked as among the most influential in the British establishment.

    Rather than accepting the evidence, or even attempting to counteract it, he makes use ot ‘Medically Unexplained Symptoms’. (MUS).

    You might think that if symptoms are ‘medically unexplained’, this indicates a need for efforts to seek the explanations.

    The psychiatric response is to capitalise the initials and call it a psychiatric condition.

    Then you make a list of diseases which have ‘Medically Unexplained Symptoms’, and put ME/CFS on this list, along with Fibromyalgia, IBS, pelvic pain … not sure if multiple sensitivities is also on it.

    Then you write a report for the Commissioners of Services for Mental Health, about how MUS is a serious epidemic, costing the NHS millions, and setting out the NHS-wide network of services which must be provided to treat this epidemic. This report states that all services must be based on the biopsychosocial model. This will inevitably include CBT and GET, although both will probably be renamed…’encouragement to increase activity’? Therapy to change ‘unhelpful illness beliefs?

    And he assures these commissioners that all the expense involved will be recouped because these patients will recover.

    In view of the fact that the PACE Trial managed to slightly increase the burden of disaility payments, think of the possibilities with this new project!

    Simon Wessely is very determined to retain the power he and his group already have, over research funding, NHS funding, media presentation of ME/CFS via the Science Media Centre…and it is only the very brave who attempt to challenge it.

    Many thanks to Keith Geraghty, and in this instance, to Charles Shepherd. And to David Tuller, Julie Rehmeyer, Tom Kindlon and all others engaged in this (potentially career-destroying) task.

    Someone needs to warn the Mental Health Commissioners. Mental Health deserves all the funding it can get…those funds should not be wasted on inappropriate and damaging ‘treatments’ for under-researched medical diseases.

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