There have been many comprehensive analyses of the controversial PACE trial data over the last few years, but with Long Covid becoming a growing concern, and sharing many similarities with ME/CFS, what follows is an accessible “primer” for anyone new to the area.
This article explains why many doctors, researchers, and patients object to the PACE trial recommendations of Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT) as treatments for ME/CFS, and why Long Covid groups are now discovering the same.
What is ME/CFS?
ME/CFS is a chronic illness that affects the immune, endocrine, and nervous systems, and for which there is currently no cure. It commonly begins after a virus, and of the 15–30 million sufferers worldwide, 25% are housebound or bedbound, and 75% are unable to work.
Its symptoms include widespread pain, loss of cognitive function, paralysis, vertigo, sensitivity to sound, light, and touch, nervous system and digestive dysfunction, and much more. Despite being more commonly known as Chronic Fatigue Syndrome, its cardinal symptom isn’t simply fatigue, but Post Exertional Malaise, a profound worsening of symptoms after exertion.
What is the PACE trial?
The PACE Trial was a trial of behavioural and psychiatric treatments for ME/CFS, which examined 641 patients. The researchers compared standardised specialist medical care (SMC) alone, to SMC plus either Adaptive Pacing Therapy, Cognitive Behavioural Therapy, or Graded Exercise Therapy.
The PACE authors were among a prominent group of mental health professionals in the UK who argued that ME/CFS, although classified as a neurological illness by the World Health Organisation, was actually caused by severe physical deconditioning. They believed that, rather than suffering from a physical illness, patients’ “unhelpful” and “dysfunctional” sickness beliefs were the cause of their symptoms.
As such, they expected that the CBT and GET groups in the study would experience the largest improvements, and eventually in 2011 they reported that this is what the trial had shown. Immediately, this was controversial, as patient groups for many years had shown that exercise outside of available energy limits (GET) made patients worse, while CBT didn’t have any effect at all.
Funding, Timeline, and Design
The PACE trial cost £5 million, and to date it is the most expensive and influential piece of research into ME/CFS ever conducted.
It was funded by the UK Medical Research Council, the Department of Health and Social Care for England, the Scottish Chief Scientist Office, and — uniquely and controversially for a clinical trial — the Department for Work and Pensions (DWP).
Patient recruitment began in 2005, and data collection was completed in 2010. The main study outcomes were published in the medical journal The Lancet in 2011.
By the time the study was published, the National Institute for Health and Care Excellence (NICE) had already been recommending GET and CBT as a standard treatment in the UK for four years. The PACE trial was simply expected to confirm that these treatments worked.
Initial Impact in Medicine and the Media
When the first PACE trial paper was published in 2011, researchers Professor Michael Sharpe and Professor Trudie Chalder held a press conference, in which Professor Chalder claimed:
“Twice as many people on graded exercise therapy and CBT got back to normal.”
These claims were reported widely in the UK and international press. The Daily Mail wrote that “Fatigued patients who go out and exercise have the best hope of recovery”, while according to the British Medical Journal’s report on the trial, some participants were actually “cured”.
Many other PACE papers followed, and when long-term follow-ups were published in The Lancet Psychiatry in 2015, The Daily Telegraph ran a front-page story with the headline “Exercise and Positivity Can Overcome M.E.”. The piece went onto say that:
“Chronic Fatigue Syndrome is not actually a chronic illness, and sufferers can overcome symptoms by increasing exercise and thinking positively, Oxford University has found”.
While the UK had already adopted the GET and CBT models, following the PACE trial publication, this protocol spread worldwide. In the US, the Mayo Clinic, Cleveland Clinic, Kaiser Permanente, and WebMD started to recommend the treatments too.
Campaign and Tribunal
Despite its lauding by the trial authors and in the press, the results of the PACE trial directly contradicted many decades of patient experience, in which exertion was found to cause profound and sometimes permanent worsening of symptoms.
Because of this dichotomy, patient groups, charities, doctors, and researchers around the world requested the release of the PACE trial raw data, so that it could be fully analysed independently. These requests were initially denied.
Multiple Freedom of Information requests followed, and in 2015 one of the PACE authors, Peter White, lobbied the UK government through his university, the Queen Mary University of London (QMUL) and the Science Media Centre, to restrict the Freedom of Information Act for universities - especially for controversial research - in an attempt to stop the data from being released.
In 2015, Dr Richard Smith, a former editor of the British Medical Journal, said that QMUL’s failure to release the data lead to “the inevitable conclusion that they have something to hide.”
Finally, in 2016, a tribunal ruled that the data must be shared, after QMUL spent £200,000 on legal fees to prevent it.
Criticisms of the Study Data
Once the data was finally released, criticisms of the way the PACE trial was conducted came from all quarters. The full PACE data led to over 40 scientists writing to The Lancet to raise serious concerns about the study, and asking for a new independent analysis of the results to be carried out.
David Tuller, a senior fellow in public health and journalism at UC Berkeley’s Center for Global Public Health, published an excoriating 14,000 word report detailing the numerous and dangerous errors in the study.
Dr James Coyne, Professor of Health Psychology at the University Medical Centre Groningen, described the trial as “a wasteful train-wreck of a study.”
And after Professor Jonathan Edwards of UCL reviewed the data, he declared that:
“PACE is valueless for one reason: the combination of the lack of blinding of treatments and choice of subjective primary endpoint. Neither of these alone need be a fatal design flaw, but the combination is”.
He went onto state that:
“The authors have not been meticulous in trying to avoid bias that might arise. On the contrary, they appear to have acted in ways more or less guaranteed to maximise bias.”
Among the many critiques, the most damning fall into the following categories:
1. That the authors used the Oxford Criteria to select trial patients
The Oxford Criteria is an out-of-date set of diagnostic criteria for the diagnosis of Chronic Fatigue Syndrome, which was established by a group made up of mostly psychiatrists (including PACE trial author Professor Michael Sharpe) in 1991.
This criteria recognises two broad syndromes for research purposes: Chronic Fatigue Syndrome, and Post-Infectious Fatigue Syndrome. In their definition of CFS, disabling fatigue is the primary symptom, which needs to have been present for at least 6 months to warrant a diagnosis.
Post-Infectious Fatigue Syndrome they identify as a sub-type, which “either follows an infection or is associated with a current infection”.
The problem with the Oxford Criteria, is that it is no longer used to diagnose ME/CFS patients, as it doesn’t feature the defining feature of ME/CFS (Post exertional malaise), and includes too many other chronic diseases within its definition.
In 2015, a research report stated:
“The Oxford CFS case definition is the least restrictive, and its use as entry criteria could have resulted in the selection of participants with other [different] fatiguing illnesses, or [other] illnesses that resolve spontaneously with time.”
Another analysis said that:
“For every 15 patients selected under Oxford criteria, 14 will be false positives when compared to [the more stringent] Canadian Consensus Criteria.”
2. The authors changed their criteria for effectiveness half-way through
Partway through the trial the authors introduced post-hoc “normal ranges” for fatigue and physical function. These ranges have been heavily criticised for having thresholds so low, that patients could theoretically worsen during the trial, and yet still be within these “normal” ranges of fatigue, and therefore marked as recovered.
The new “normal” range of physical function introduced by the authors (and measured on the SF-36 100-point scale) was 60 and above, even though patients had to have a score of 65 or lower to be qualified to enter the trial in the first place. To put that into perspective, a score of 60 is close to the mean physical function score (57) for patients suffering from class II coronary heart failure, so is hardly an example of good health.
3. Use of subjective main outcome measures
The PACE trial is further criticised for having subjective primary analyses in an unblinded trial. Subjective measures are known to be susceptible to bias, which can arise from patient expectations and social pressure, either knowingly or unknowingly exerted by the researchers.
During the trial, the CBT and GET groups, but not the others, were told that there was nothing to stop them from recovering if they gradually increased their activity.
Critics have argued that these different expectations could have inflated patient’s self-assessments at the end of the trial, compared to the groups that weren’t told that they were going to recover, and therefore perceived less expectation of recovery from the researchers as a result.
4. Conflicts of interest and lack of informed consent
The 42 scientists and clinicians who initially wrote the open letter to The Lancet, criticised the authors’ failure to disclose a potential conflict of interest to trial participants.
“The investigators violated their promise in the PACE protocol to adhere to the Declaration of Helsinki, which mandates that prospective participants be ‘adequately informed’ about researchers’ “possible conflicts of interest.
“The main investigators have had financial and consulting relationships with disability insurance companies, advising them that rehabilitative therapies like those tested in PACE could help ME/CFS claimants get off benefits and back to work.
“They disclosed these insurance industry links in The Lancet but did not inform trial participants, contrary to their protocol commitment. This serious ethical breach raises concerns about whether the consent obtained from the 641 trial participants is legitimate.”
Impact on Patients
Far from being a set of harmless behavioural interventions which are at best curative, and at worst useless, an initial survey conducted in 2012 by the ME Association showed that 74% of patients had their symptoms worsen after a course of GET.
Some patients involved in the PACE trial also claim that while they were able to walk at the start of the course of graded exercise, they eventually dropped out in wheelchairs, or became bedbound as a result.
But the more insidious effect of the PACE trial, is that thanks to its claim of having produced a cure, biomedical research into the disease isn’t prioritised for funding. Doctors and medical students are taught that these behavioural interventions work, and are unaware of the harm they cause when they prescribe them to patients.
And journalists around the world have unknowingly been complicit in maligning severely ill patients as malingerers, or as “just a bit tired” and in need of some positive thinking. This is already having its impact on Long Covid post-viral patients, who are coming up against the same attitudes and disbelief today.
Following the PACE trial controversy, in 2019, MP Carol Monaghan brought the plight of ME/CFS patients to Parliament.
As a result, MPs voted unanimously to increase biomedical research funding into the illness, and NICE embarked upon a review of its treatment guidelines, which have recommended CBT and GET since midway through the PACE trial.
As of 2020, the revised draft guidelines state clearly that GET shouldn’t be offered as a treatment for ME/CFS, and instead NICE highlight the importance of ensuring that people remain within their “energy envelope” when undertaking activity, marking a return to the former “adaptive pacing” knowledge that patient groups championed pre-influence of the PACE trial.
The full guidelines are scheduled to be finalised and released in August this year, but in the meantime:
· A growing number of international health authorities, including the US Centers for Disease Control and the Dutch Health Council, have stopped recommending CBT and/or GET as suitable treatments for M.E.
· In 2019, leading American clinicians who specialise in M.E. “unanimously agreed that the two PACE treatments are inappropriate and possibly harmful for patients.”
Why does this matter for Long Covid?
While many Long Covid patients have testable damage to their internal organs following severe infection and hospital admittance, an ever-growing subset of sufferers experienced milder acute symptoms, but nevertheless developed troubling chronic problems afterwards. This follows the same pattern repeated in ME/CFS patients over many decades, who initially experienced glandular fever/mono, the flu, swine flu, an enterovirus or a respiratory virus, and subsequently became chronically unwell.
In fact, a recent study showed that out of 29 post-viral ME/CFS symptoms, Long Covid sufferers report 25 of the same symptoms, on average. The simple fact is, that many Long Covid sufferers are now, or will later, meet the criteria for ME/CFS. They need to be aware of the danger of pushing themselves into exercise therapy, when the only evidence for its efficacy is a deeply flawed study by a group of prominent mental health professionals, which is currently under review, and is now widely accepted outside of the UK to be bad science, and a danger to patients.
· David Tuller’s analysis of the PACE Trial: http://www.virology.ws/2015/10/21/trial-by-error-i/
· News report on the release of the PACE trial data: https://inews.co.uk/news/health/tribunal-chronic-fatigue-syndrome-data-released-18748
· More information on PACE trial controversy: https://me-pedia.org/wiki/PACE_trial#cite_note-EdwardsJC20151101-65