The incredible story of the PACE trial for ME/CFS | Part 1

How a phase 3 clinical trial went off the rails and led patients around the world to receive inappropriate therapies which, in some cases, caused them profound and lasting harm.

Continues from the Introduction.

The PACE trial

The PACE trial was a phase three clinical trial which tested three treatments for chronic fatigue syndrome. The three treatments were:

• Cognitive behaviour therapy (CBT), a type of talk therapy

• Graded exercise therapy (GET), a program of exercise which starts off gently then gradually increases in intensity

• Adaptive pacing therapy - this one is difficult to explain, but it turns out not to be very important anyway, so I’m simply going to leave it out.

All the trial participants also received standard medical care. There was also a fourth group which only received standard medical care, which served as the control group.

Planning for the trial began in 2004. A protocol which outlined how the trial was to be conducted was published in 2007, the trial ran from 2006 to 2010, and the first and most important scientific paper to come out of it was published in The Lancet in 2011.

Further reading: PACE Trial, Queen Mary University of London

What medical condition did people who participated in the PACE trial have?

You’d expect this to be a simple and straightforward question to answer but, well, it isn’t.

As I write this in 2023, medical experts don’t use the term ‘chronic fatigue syndrome’ anymore, in part because patients find this term offensive. Patients have always preferred the term myalgic encephalomyelitis (ME). The modern medical term is ME/CFS, and I’ll mostly use that one in this article.

It’s not just a question of terminology, it’s a question of what, exactly, this illness is. The PACE trial investigators used a definition of chronic fatigue syndrome known as the Oxford Consensus Criteria, which was created in 1991. According to the Oxford criteria, a person can be diagnosed with chronic fatigue syndrome if they have debilitating chronic fatigue for six months, plus any one of a list of other symptoms. There is a huge problem with this definition: it’s not specific enough. Chronic fatigue is very common. It’s a symptom of a large number of illnesses, from cancer to viral infections to depression, and it’s also found in people who aren’t sick at all, but who simply work too hard and don’t get enough sleep.

No-one uses the Oxford criteria anymore. There are several modern definitions of ME/CFS, but all of them require the presence of a unique and specific symptom called post-exertional malaise (PEM), which I’ll talk about more further on.

Because of its overly-broad entry criteria, it isn’t clear how many of the people who took part in the PACE trial actually had ME/CFS.

The PACE trial investigators and their views of ME/CFS

Nineteen scientists worked on the PACE trial. There were three principal investigators: professor of psychological medicine Peter White, professor of cognitive behavioural psychology Trudy Chalder, and psychiatrist Michael Sharpe.

All three principal investigators had devoted much of their careers to studying and treating the illness they called ‘chronic fatigue syndrome’. They belonged to what is sometimes called the Wessely School, which created the biopsychosocial model of chronic fatigue syndrome. Their core belief about this illness is as follows:

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Chronic fatigue syndrome usually begins with a viral infection. The viral infection causes the patient to spend much of their time in bed, perhaps for several weeks, and the patient becomes deconditioned. When the patient finally gets out of bed, they find that they have a lot of aches and pains and it’s difficult to move. This is caused by deconditioning, but the patient mistakenly believes that they are still sick. They therefore spend even more time in bed, mistakenly thinking that they need to convalesce. They become even more deconditioned, setting up a vicious cycle. Other factors feed in to this vicious cycle: the patient may focus too much on their symptoms, they may have depression which makes it harder for them to get active, and they may receive ‘secondary gains’ from being sick, such as not having to go to work or getting special attention from loved ones.

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There was never any convincing evidence to support this theory, and people living with ME/CFS have always said that it is nonsense. This theory has nevertheless been widely held by medical professionals since it was first developed in the 1980s and 1990s. It must be pointed out that this theory is very convenient to medical institutions who wish to shirk their responsibility to provide medical care to patients, to research institutions who wish to shirk their responsibility to carry out medical research, to disability insurance companies who wish to avoid paying out long-term disability benefits, and to politicians and government departments who are committed to cutting disability benefits and getting people back into work.

Further reading: The ‘cognitive behavioural model’ of chronic fatigue syndrome: Critique of a flawed model, Health Psychology Open

The results of the PACE trial

Several scientific papers came out of the PACE trial. The first and most important one, ‘Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial’, was published in 2011. The results: both cognitive behavioural therapy (CBT) and graded exercise therapy (GET) helped some patients to significantly improve.

This result was more momentous than it might seem at first glance. There was furious debate over whether CBT and GET were effective therapies for ME/CFS. At a deeper level, the debate was really over whether ME/CFS was a psychological (or behavioural or psychosocial) illness, or whether it was a chronic medical condition like, say, multiple sclerosis or diabetes.

There had been quite a few studies similar to the PACE trial before, with similar results, but they were relatively small, while the PACE trial was large and well-funded. With over six hundred participants, it was statistically powerful enough to guide the treatment of patients in clinical settings. Moreover, the scientists who had conducted it were experienced and well-regarded. It had the backing of the UK’s Medical Research Council, and it was published in a highly prestigious medical journal, The Lancet. The PACE trial seemed to settle the debate over ME/CFS (or chronic fatigue syndrome, or whatever you want to call it) once and for all.

Media response

The PACE trial’s results were announced at a press conference and the story was picked up by UK and international news media. The Independent's headline read: ‘Got ME? Just exercise, say scientists.’ The Guardian's was ‘Study finds therapy and exercise best for ME’, while The New York Times went with ‘Psychotherapy Eases Chronic Fatigue Syndrome, Study Finds’. The author of that last one was David Tuller, who comes into the story again later.

The message was clear: ME/CFS was a relatively minor illness, it was psychological, and people suffering from it could be expected to return to health after a course of counselling and exercise.

Over the next few years, the PACE trial profoundly influenced the clinical treatment of people with ME/CFS in the UK and around the world, either reinforcing existing recommendations for CBT and GET, or influencing a switch to such recommendations. For example the NHS, NICE, the CDC, Mayo Clinic and Kaiser Permanente all endorsed CBT and GET for ME/CFS in this time period.

Further reading: 
• Bad science misled millions with chronic fatigue syndrome. Here’s how we fought back, STAT
• The PACE trial, MEpedia

Reality check: what ME/CFS is actually like

At this point in the story we need a reality check. The PACE trial report painted ME/CFS as a relatively minor illness which was psychological in nature, and which improved with counselling and exercise. This picture was at odds with the experiences of real people living with the condition.

It's difficult to describe ME/CFS to people who don't have it. There is a profound lack of energy which is sometimes called ‘fatigue’, but it’s nothing like the fatigue that healthy people experience if they work too hard or don’t get enough sleep; it’s more like the fatigue of cancer patients undergoing chemotherapy. There is a very long list of other symptoms - including brain fog, muscle and joint pain, unrefreshing sleep, tinnitus, gastrointestinal problems, headaches, dizziness, muscle weakness, light and noise sensitivities - but reading a list of symptoms doesn’t give you much insight into what the illness is actually like. I think the most useful question to ask is: “What do you lose, if you get ME/CFS?”

There are different levels of severity. If you get mild ME/CFS you might manage to hold onto your job or continue going to school (perhaps with reduced hours) but to do it you’ll have to give up everything else – social activities and time with family, hobbies, sports, even watching TV – and spend every spare moment resting.

If you get moderate ME/CFS you won’t be able to work, and every day will be a long, drawn-out struggle to carry out basic self-care tasks like taking a shower or preparing and eating a simple meal. If you get severe ME/CFS you’d better hope your family will care for you, because you’re going to be spending most of your waking hours in bed, and you won’t be able to do much of anything. At the most severe end, people become so weak they cannot move or speak, they lose the ability to eat and drink, and require tube feeding. In some cases, people die.

The PACE trial report claimed that some people with ME/CFS improved after doing GET. At the time that report was published, CBT and GET were already the standard treatments for ME/CFS in England and throughout the UK. Nearly everyone who had ME/CFS had already tried to exercise themselves back to health. It didn’t work. In some cases, it made them sicker. (I’ll go into this in more detail further on.)

Further reading: 'Why we shouldn’t call it 'chronic fatigue syndrome', Rivka Solomon, STAT

Chronic fatigue syndrome clinics in England, 2001 - 2021

From the early 2000s to 2021, CBT and GET were the recommended treatments for ME/CFS in the UK. There were specialist clinics scattered throughout the country, run by the National Health Service (NHS), where patients met with clinicians who taught them CBT and encouraged them to gradually increase their activity levels.

The CBT was of a particular type. In ordinary, garden-variety CBT, the therapist encourages the patient to challenge disturbing thoughts. For example, a person with depression might find themself thinking "I'm worthless." The therapist helps them find ways to challenge this, perhaps by listing things they’ve done that they’re proud of, or by thinking of friends and loved ones who care about them and value their company.

The type of CBT used with ME/CFS patients was... different. It was based on the theory that these patients pay too much attention to their physical symptoms. Therapists encouraged patients to ignore their feelings of pain and exhaustion and stick to an exercise plan or activity plan. Patients who complained that they felt physically shattered were promised: "If you push through this, you'll start to see real improvement."

Patients were not told that the therapy was controversial. They weren't advised that many experienced clinicians around the world insisted that patients with ME/CFS should rest and carefully pace their activities. They weren't told about post-exertional malaise, a unique symptom of ME/CFS whereby exertion of any type can trigger a relapse, with a delay of usually twenty-four to forty-eight hours, and lasting anywhere from a few hours, to a day or two, to weeks, months, or a lifetime. Some of the people who attended these clinics became housebound or bedbound.

Further information:
• 25% ME Group stance on exercise, 25% Group
• Assessment of Post-Exertional Malaise (PEM) in Patients with Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS): A Patient-Driven Survey, Diagnostics

How the PACE trial affected the clinical treatment of people with ME/CFS in the UK

The PACE trial didn't change the way people with ME/CFS in the UK were treated, it reinforced the status quo. But it did prevent change from happening. Patient groups continued to demand medical research and medical treatment, but they were ignored; after all, the best research seemed to show that they didn't need medical treatment, just counselling and exercise. Research into problems in the brain, nervous system and immune system in people with ME/CFS was ignored, because the PACE trial seemed to show that the pathophysiology associated with the condition was irrelevant. Patients insisted that exercise caused them real harm, but this was ignored because it contradicted the PACE trial.

To this day, ME/CFS is hardly taught in medical schools, in part because the PACE trial seemed to show that the condition was to be dealt with by counsellors and physiotherapists, not by doctors. The NHS has made no effort to teach its doctors and nurses anything at all about the condition. There are no doctors specialising in ME/CFS working within the NHS; doctors who wish to help these patients are forced to work privately.

Graded exercise therapy (GET) and post-exertional malaise (PEM)

I’d like to step back for a moment and talk about GET in general, not just in the context of ME/CFS. GET is a way for people who are unfit or deconditioned to become fitter. The concept is simple: you start at a level of activity that you can do without too much difficulty, and then you increase the intensity by about 10% each week. It works because over time the body adapts to physical activity by becoming stronger and using oxygen more efficiently. GET is fantastic for people who are inactive who want to start building up some physical fitness. It’s also great for people who have had a long hospital stay and for people who have survived a stroke. It tends to be helpful for people with almost any serious illness, from cancer to multiple sclerosis and even, in some cases, heart disease.

But when people with ME/CFS tried GET they found that it simply didn’t work. The exercise provoked the awkwardly-named symptom post-exertional malaise (PEM), also called post-exertional symptom exacerbation. PEM is essentially a relapse, provoked by over-exertion, with a delay of a day or two. PEM can last anywhere from a couple of days to weeks, months, or years. When people with ME/CFS did a GET program, they were constantly pushing themselves into more and more severe PEM. Furthermore, their bodies did not adapt to increased activity by becoming fitter and stronger. When they increased the intensity of their exercise sessions they had to push themselves harder, and the more intense workouts provoked more intense and longer-lasting PEM. By exercising, they made themselves sicker. And some found that, when they finally gave up and stopped doing the exercise, the PEM never went away. GET had made their ME/CFS permanently more severe.

I should note that the exercise sessions we’re talking about would look very gentle to an outside observer. But the intensity of exercise is subjective. Most people would think that walking fifty meters is very easy, for example, but if you have a sprained ankle, then it’s agony.

Further information:
• When exercise causes harm, Bateman Horne Center short video
• Post-exertional malaise, Bateman Horne Center video series

Early opposition to the PACE trial

Given these realities, it won’t come as a surprise that not everybody was happy about the PACE trial.

In 2010 British professor of medicinal chemistry Malcolm Hooper filed a formal complaint with the Medical Research Council, the PACE trial’s main funder. At this point the PACE trial had not yet been completed, but Hooper’s complaint was based on its protocol (a plan which laid out how the trial was to be conducted) and on the previous work of the investigators. Hooper’s concerns included that:

• The PACE trial was opposed by patients and by organisations that supported them.

• The PACE trial investigators believed that ME/CFS was a behavioural disorder, despite considerable evidence of physiological abnormalities in people with the condition.

• The PACE trial’s principle investigators had links to the insurance industry, which was determined to avoid making long-term insurance payments to people with ME/CFS. In particular, they had links to the insurance company UNUM Provident. Since 1993, UNUM Provident had advised the UK government’s Department for Work and Pensions (DWP) on how to reduce disability payments to people with ME/CFS.

Hooper’s complaint was backed by a 400-page report, ‘Magical Medicine: How to Make a Disease Disappear’ written by himself and the retired NHS clinician and ME advocate, Margaret Williams.

Shortly after the PACE trial’s publication, Hooper submitted a 70-page formal complaint to the Lancet about the PACE trial. When Margaret Williams called the Lancet to discuss the complaint, the Lancet’s executive editor, Dr Stuart Spence, threatened her with a lawsuit. He warned: “You’d better be damned sure that you’re right or The Lancet’s lawyers will be on you if it goes into the public domain.” Hooper and Williams made the complaint public anyway. The lawsuit Spence had warned of never materialised.

ME charities that were asked by the press to comment on the PACE trial responded strongly. A spokesperson for Action for ME, speaking in The Guardian, pointed out that in a survey of more than four thousand people with ME, 34% of those who had tried GET reported that it made them worse. In The Independent, the ME Association argued that the PACE trial’s findings were based on an outmoded model of the illness.

A number of science-savvy people with ME/CFS wrote directly to The Lancet to point out various problems with the PACE trial, and some of their letters were published in a May 2011 issue. The problems they pointed out were complex, but I’ll list simplified versions of some of their arguments:

• The PACE trial authors claimed that trial participants had increased physical activity, but this might not actually be true. The data on exercise came from self-reports, and people who are being pressured to follow an exercise program they find difficult or painful might tend to over-state how much they are doing.

• The PACE trial authors claimed that exercise was safe, but did not provide adequate evidence that this was true.

• The 2011 scientific report on the PACE trial was very different from what the investigators had originally promised to do in their 2006 protocol.

• The PACE trial authors used a very strange definition of ‘recovery’. The health of the study participants had been evaluated using the SF-36 questionnaire. At the beginning of the trial a score of 65 or lower was interpreted to mean the patient was sick, but at the end of the trial a score of 60 or higher was taken to mean the patient had ‘recovered’. It was possible for a study participant to get sicker over the course of the trial, and yet be counted as ‘recovered’!

Further reading: 'The PACE trial in chronic fatigue syndrome' at The Lancet, responses by:
• Jane Giacoumakis
• John T Mitchell Jr
• Sarah M Feehan, on behalf of the Liverpool ME Support Group
• Andrew James Kewley
• Bart Stouten, Ellen M Goudsmit and Neil Riley
• Tom Kindlon

The Lancet’s editorial team gave space to patients’ concerns, only to dismiss them. In an editorial titled Patients’ power and PACE, a Lancet editor wrote:

Once every few years, we publish a paper that elicits an outpouring of consternation and condemnation from individuals or groups outside our usual reach. The latest topic to have caused such a reaction is chronic fatigue syndrome…

The response to the trial's publication was swift and damning. “When is the Lancet going to retract this fraudulent study?” demanded a Facebook group. A 43-page complaint (now available via Wikipedia) branded the trial “unethical and unscientific”. There were 44 formal letter submissions, eight of which we publish today…

But the editor concluded that:

The researchers should be praised for their willingness to test competing ideas and interventions in a randomised trial. The evidence might even suggest that it is the critics of the PACE trial who have formed their opinions first, ignoring the findings of this rigorously conducted work.

Over the next few years, the ME community continued analysing the PACE trail and pointing out its flaws.

Further reading:
• M.E. Analysis: Evaluating the results of the PACE trial, 2011, archived by WaybackMachine
• People want to learn as much as possible from the PACE trial for chronic fatigue syndrome, Tom Kindlon, BMJ Letters, paywalled
• Julie Rehmeyer, Epistemically Challenged, December 2015
• Doubts over the validity of the PACE hypothesis, Robert Courtney, The Lancet Psychiatry, April 2015
Further viewing:
• The PACE trial, a series of short videos by ME Analysis. (For a light-hearted take on a serious topic check out the international cartoon sing-a-long).

In 2013 there was a parliamentary debate over the PACE trial in the UK’s House of Lords. The Countess of Mar’s ten-minute speech at the beginning of this debate is a concise and detailed summary of all that is wrong with the PACE trial.

However, all this criticism largely ignored in the medical and scientific worlds. The PACE trial continued to be the last word on ME/CFS for several years. Then in 2015, things began to change.

The story continues in part 2…

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Image credit: The PACE Trial by ME Analysis