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’ 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:
|Error||Category of error||Description of error|
|1||Ethical 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).|
|2||Ethical 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.|
|3||Ethical 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.|
|4||Use 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).|
|5||Inadequate 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.|
|6||Changing the primary outcomes of the trial after receiving the raw data.||Altering outcome measures mid-trial in a manner which gave improved outcomes.|
|7||Changing 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.|
|8||The 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.|
|9||Inadequate control||Sending participants newsletters promoting one treatment arm over another, thus contaminating the trial.|
|10||Inadequate control||Lack of comparable placebo/control groups with inexperienced occupational therapists providing a control treatment and experienced therapists provided CBT.|
|11||Inadequate control||Repeatedly informing participants in the GET and CBT groups that the therapies could help them get better.|
|12||Inadequate control||Giving patients in the CBT and GET arms having more sessions than in the control group.|
|13||Inadequate control||Allowing therapists from different arms to communicate with each other about how patients were doing.|
|14||Lack of transparency||Blocking 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.
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/
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
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
- 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.
- The authors and sponsors have done a disservice to science and to patients that will be hard to forget.
- An apology is the least that the principal investigators can do to make amends for this dreadful piece of pseudo-science.
- The universities involved should return the public funds that were wasted on the PACE trial project.
- 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.