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