PACE trial

The PACE Trial (short for "Pacing, graded Activity, and Cognitive behaviour therapy; a randomised Evaluation" was a large-scale trial of treatments for people with Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME).

The study compared standardised specialist medical care (SMC) alone to SMC plus Adaptive Pacing Therapy (APT), Cognitive Behavioral Therapy (CBT), or Graded Exercise Therapy (GET). The experimenters hypothesised that the CBT and GET groups would do best, and reported that this is what the trial's results showed  but the claim has proved controversial.

The PACE trial dominates clinical policy in the United Kingdom and other countries, in both government funded health care and private medical insurance.

Background
The PACE trial was funded by the UK Medical Research Council, Department of Health for England, Scottish Chief Scientist Office, and - apparently uniquely for a clinical trial - the Department for Work and Pensions. It cost £5 million and is the most expensive piece of research into ME/CFS ever conducted.

Recruitment of patients began in March 2005 and data collection was completed in January 2010. The study protocol was published in BMC Neurology in 2007. The main study outcomes were published in The Lancet in 2011 and the experimenters continue to publish papers on the trial.

The principal investigators were Professors Peter White, Trudie Chalder, and Michael Sharpe. Although not an author, Professor Simon Wessely provided feedback on their report. He stated in November 2015 that "there are also more trials in the pipeline".

Study design
641 patients were randomised into four groups in the study. All received specialist medical care (SMC), which consisted of medication for symptoms such as insomnia and pain, and general advice to avoid extremes of rest and inactivity. One group received SMC alone. Patients in another group additionally received adaptive pacing therapy (APT), and were advised to stay within the limits of activity imposed by the disease to give their bodies the best chance of recovery. The other two groups were both told that they were not ill but deconditioned, and that if they gradually increased their activity, there was nothing to prevent their recovery. The cognitive behavioural therapy (CBT) group focused on addressing their presumed fear of activity while the graded exercise (GET) group focused on increasing their activity in a structured manner, with regular aerobic exercise as the eventual goal.

Patients in the APT, CBT and GET groups were offered up to 14 sessions with a therapist over a six-month period, to support them in following their therapy programmes, with a top-up session at 36 weeks. They also received a lengthy manual  explaining their therapy. All participants were offered at least three sessions of SMC.

Patients were assessed at baseline, 12 weeks, 24 weeks and 52 weeks. The main outcome measures were self-rated fatigue and physical function. Secondary measures included the study's objective variables such as a six-minute walking test, a fitness test and economic measures including the number of days of work lost due to fatigue, and the receipt of sickness benefits.

Patients were also followed up (using subjective ratings only) at least two years after randomisation.

Findings
The trial's results showed that patients in the CBT and GET groups improved more in self-rated fatigue and physical function than the APT or SMC-only groups. Apart from the GET group improving slightly more than the others on the six-minute walking test, all of the study's objective measures  and the long-term follow-up data (self-ratings of fatigue and physical function) showed no difference between groups.

The authors reported, in a 2013 paper specifically about recovery, that 22% of patients in the CBT and GET groups had recovered following these therapies, compared to 8% in the APT group and 7% in the SMC-only group.

Impact
The PACE trial and other studies that use the Oxford criteria for diagnosis of ME/CFS have had major international impact on popular perceptions of the disease and also on public policies toward treating and researching it.

Media


On February 27, 2011, when the first PACE trial paper was published, researchers Michael Sharpe and Trudie Chalder held a press conference  to discuss their findings. Chalder stated, “twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal.” That assertion has been criticized for grossly overstating the study's actual findings.

The claims made about the study were covered in the UK and international press. For example, The Daily Mail stated, "Fatigued patients who go out and exercise have best hope of recovery", while The New York Times declared "Psychotherapy Eases Chronic Fatigue Syndrome". According to the British Medical Journal's report on the trial, some participants were "cured."

Many other PACE papers followed, although with relatively little media attention until October 2015, when long-term follow-up results were published in The Lancet Psychiatry. The Daily Telegraph ran a front-page story with the headline, "Exercise and positivity can overcome ME." The piece stated, "Chronic Fatigue Syndrome is not actually a chronic illness and sufferers can overcome symptoms by increasing exercise and thinking positively, Oxford University has found". The article quoted Professor Sharpe describing ME as a “self-fulfilling prophesy” that happens when patients live within their limits. The article was altered following public pressure but no formal retraction was made.

In the UK the Science Media Centre is a government-funded body that describes its purpose as being to improve science journalism. Its reporting on ME/CFS has been criticized for bias towards a psychological etiology for the disease.

Influence on treatment
The sheer size of the PACE trial means that it dominates the evidence base in ME/CFS. Together with other studies of CBT and GET, it is highly influential in UK clinical policy and that of many other countries, both in terms of healthcare provided by government and by private medical insurance.

In the UK, the NICE guidelines for NHS-provided care recommend CBT and GET for ME/CFS. They were published in 2007, before the PACE trial was conducted, but the evidence was based on a few small trials and was considered "somewhat limited". The ME Association has asked for the guidelines to be updated to take into account new treatment evidence, noting, "we assume that the guideline surveillance review that took place in March 2011, and which followed publication of the PACE trial in February 2011, simply ‘rubber stamped’ the 2007 NICE guideline recommendations on the basis that the PACE trial had supported the recommendations relating to CBT and GET." NICE responded, "we still do not feel that the evidence base is substantially evolving in this area at this time" and the guidelines currently remain on the "static" list.

In the US, CBT and GET are included in the Center for Disease Control's clinical guidelines for CFS, based on the PACE trial evidence.

Selection of patients
The PACE trial used the Oxford criteria for diagnosis. Many patients and specialist clinicians consider them overly broad, and the National Institutes of Health 2015 P2P report on ME/CFS recommended that the Oxford definition be retired for this reason.

Changes in criteria for effectiveness and recovery


The authors abandoned their protocol-specified main outcome and recovery analyses partway through the trial and replaced them with others. They have defended the changes, noting, "All these changes were made before any outcome data were analyzed (i.e. they were pre-specified), and were all approved by the independent Trial Steering Committee and Data Monitoring and Ethics committee." However, 42 scientists, in an open letter to The Lancet, stated that the changes were of "of particular concern in an unblinded trial like PACE, in which outcome trends are often apparent long before outcome data are seen. The investigators provided no sensitivity analyses to assess the impact of the changes and have refused requests to provide the results per the methods outlined in their protocol."

Most notably, 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 worsen from trial entry and yet be within these normal ranges. The "normal range" for physical function (measured on the SF-36 100-point scale) was 60 and above, even though patients had to score 65 or lower to enter the trial. A score of 60 is close to the mean physical function score (57) of patients with Class II coronary heart failure.

"'The average age of participants in the PACE trial is about 39 years old; normative data suggest that people in this age group should have SF-36 scores of about 93. Yet the new 2013 “normal” is a score of 60.'"

The PACE authors used the "normal ranges", in conjunction with other thresholds, to define clinical effectiveness in the Lancet paper and recovery rates in a later paper in Psychological Medicine.

All Freedom of Information requests to the authors for the main outcome and recovery results according to the protocol-specified analyses, or for the underlying data so that others could conduct the analyses, have been refused.

Use of subjective main outcome measures
The study has been criticised for having subjective primary analyses in an unblinded trial. Subjective measures are known to be susceptible to bias, as can arise from expectations and social pressure. 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, and critics have argued that these differential expectations could have inflated their self-assessments.

Conflicts of interest and lack of informed consent
The forty-two scientists and clinicians who wrote an open letter to the Lancet complaining about the PACE trial criticized the study authors' failure to disclose a potential conflict of interest to trial participants. They wrote:

"'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.'"

Newsletter to participants
The investigators published newsletters for participants   while the trial was still underway. Critics have said that the material in the third newsletter could have influenced patients' self-reported outcomes. It included a number of positive testimonials from patients in the trial, but without naming their therapies. The PACE authors have argued that this meant that there would be no bias in favour of CBT and GET but Professor James Coyne has dismissed the idea that bias would be expected to affect all four groups equally.

The newsletter did, however, announce that the new NICE guidelines, "based on the best available evidence... recommended therapies [that] include Cognitive Behavioural Therapy, Graded Exercise Therapy and Activity Management." There was no explanation of what "Activity Management" was: no group had that title in the PACE trial. Dr. Bruce Levin, a professor of biostatistics at Columbia University and an expert in clinical trial design, said, “To let participants know that interventions have been selected by a government committee ‘based on the best available evidence’ strikes me as the height of clinical trial amateurism”. The newsletter also contained a less than positive assessment of research on the possibility of an infectious component of ME/CFS, including research by Jose Montoya on herpesviruses and by John Chia on enteroviruses. The newsletter said of Dr Chia's work, for example, "The laboratory work looked convincing, but many patients had significant gastro-intestinal symptoms and even signs, casting some doubt on the diagnoses of CFS being the correct or sole diagnosis in these patients." It is possible that this negative view of evidence of an ongoing infection would have made the rationale for APT appear less plausible and that for CBT and GET more plausible, thus biasing the participants.

An account of another study, in contrast, gave a positive assessment of CBT, saying "cognitive behaviour therapy was associated with an increase in grey matter of the brain and this increase was associated with improved cognitive function".

Risks and side effects
A survey conducted by the ME Association in 2012 showed that 74% of patients had their symptoms worsen after a course of GET. In contrast, the PACE trial found no apparently meaningful difference in rates of adverse events between the four trial groups, suggesting that APT, CBT and GET added no risk to SMC alone (since all four groups received SMC). However, critics have questioned whether patients actually increased their activity sufficiently in the CBT and GET groups to trigger many serious adverse events: the lack of improvement in the step-fitness test in all groups indicates that this is distinctly possible.

Response to criticism
The trial investigators have replied to criticism of the trial on a number of occasions, in response to letters to The Lancet concerning their main analyses, Psychological Medicine concerning their recovery analyses, and Lancet Psychiatry concerning their secondary mediation analyses and long-term follow-up paper. A letter to the BMJ by Tom Kindlon drew a reply from the authors that in turn received 31 responses of its own.

The investigators have also responded to a 14,000-word critique by public health expert and journalist Dr David Tuller. Dr Tuller wrote a rebuttal to their response. He has said, “The PACE authors have long demonstrated great facility in evading questions they don’t want to answer”.

Professor James Coyne reported that he agreed to debate the authors on health website National Elf about the trial but that they declined. Professor Simon Wessely was given the vacated National Elf spot and wrote a lengthy article praising the trial, noting that he once described it as "a thing of beauty" and saying, "We can accept that PACE was a good trial and we can have some confidence in its findings".

Controversy
The PACE Trial has been heavily criticised by patient groups and some researchers and science journalists for a number of methodological problems since its publication.

Renewed interest in the trial came in October 2015 with public health expert and investigative journalist Dr David Tuller's publication on Virology Blog of "Trial by Error: The Troubling Case of the PACE Chronic Fatigue Syndrome Study", a detailed analysis of PACE's methodological problems. Dr Tuller continues to publish articles criticising different aspects of the trial.

Scientists' open letter to The Lancet
In November 2015, scientists Ronald Davis, David Tuller, Vincent Racaniello, Jonathan Edwards, Leonard Jason, Bruce Levin and Arthur Reingold wrote an open letter to The Lancet citing "major flaws" in the original trial publication and asking for an independent re-analysis of the individual-level trial data. The journal failed to respond.

In February 2016 the open letter was re-published with 36 additional signatures from doctors and researchers including: Dharam Ablashi, Lisa Barcellos, James Baraniuk, Lucinda Bateman, David Bell, Alison Bested, Gordon Broderick, John Chia, Lily Chu, Derek Enlander, Mary Ann Fletcher, Kenneth Friedman, David Kaufman, Nancy Klimas, Charles Lapp, Susan Levine, Alan Light, Sonya Marshall-Gradisnik, Peter Medveczky, Zaher Nahle, James Oleske, Richard Podell, Charles Shepherd, Christopher Snell, Nigel Speight, Donald Staines, Philip Stark, John Swartzberg, Ronald Tompkins, Rosemary Underhill, Rosamund Vallings, Michael VanElzakker, William Weir, Marcie Zinn and Mark Zinn.

Petitions
On October 28, 2015, MEAction launched a petition addressed to The Lancet, Psychological Medicine and the PACE trial authors, calling for an independent analysis of the data and the retraction of some of the PACE trial's "misleading claims" based on "absurd 'normal ranges' for fatigue and physical function". The petition was closed in February 2016, having gathered 11,897 signatures from people in sixty-four countries.

A US petition to the Agency for Healthcare Research and Quality (AHRQ) and the Centers for Disease Control was also launched in late 2015, asking government agencies to remove guidelines and recommendations based on PACE and other studies using the Oxford definition of ME/CFS.

Allegations of harassment
The PACE trial investigators and Professor Simon Wessely have publicly claimed they have been harassed and subjected to death threats.

However, the PACE authors and their supporters have been accused of blurring the line between harassment and legitimate criticism of the study. Documentation obtained under the Freedom of Information Act from meetings in 2013 that were attended by some of PACE’s principal investigators include a statement that “harassment is most damaging in the form of vexatious FOIs [Freedom of Information requests].” This framing of FOIA requests as harassment is widely taken to be a reference to the PACE authors, who have complained about the number of FOI requests that they have received for data and who have dismissed several as "vexatious": the Information Commissioner's Office was told that Professor Peter White “believes that the requests are clearly part of a campaign to discredit the trial” and that “the effect of these requests has been that the team involved in the PACE trial, and in particular the professor involved, now feel harassed and believe that the requests are vexatious in nature.”

The criticisms of the trial's methodology and analyses by patients and others has been referred to by the investigators - and The Lancet - as part of a campaign to undermine the the study. In an editorial comment that accompanied letters criticising the trial, The Lancet described the trial as “rigorously conducted” and questioned whether the “coordination of the response... has been born... from an active campaign to discredit the research”. In an interview on Australian national radio shortly after publication, Dr Richard Horton, The Lancet’s editor, described patients who criticised the trial as “a fairly small, but highly organised, very vocal and very damaging group of individuals”.

But some accuse the investigators of a campaign against patients, labelling them as harassers to undermine their criticisms of the trial, including Angela Kennedy and public health expert and journalist David Tuller, who has said, “Wrapping themselves in victimhood, the [PACE authors] have even managed to extend their definition of harassment to include any questioning of their science and the filing of requests for data — a tactic that has shielded their work from legitimate and much-needed scrutiny.”

Breaches of patient's data security by study investigators
In 2006 confidential PACE trial patient data was stolen from an unlocked drawer at King's College London.

Malcolm Hooper documents in Magical Medicine how in 2005 confidential patient data was erroneously released by PACE author Professor Michael Sharpe in relation to another study.

Open data commitments
The study authors have been criticised for failing to follow the requirements of the Medical Research Council (who provided significant funding for the trial) to release anonymised trial data.

The 2012 PACE cost-effectiveness paper was published in the journal PLoS One. That journal requires authors, as a condition of submitting their papers, to agree to release the anonymized trial data underlying the paper's analyses upon request. In November 2015 Professor James Coyne made a request to the PACE authors on that basis, but the authors treated his request as a Freedom of Information request and refused it. However in March 2016 the PLoS One journal confirmed they had requested the investigators to release the trial data, as they committed to do prior to publication.

Freedom of Information requests
The PACE trial investigators have been asked for 160 pieces of separate information in 35 Freedom of Information requests since 2011. They have dismissed at least three of these claims as "vexatious".

A ruling by a UK government body, the Information Commissioner's Office (ICO), on 27 October 2015 ordered Queen Mary University of London (QMUL, the institutional base of the PACE trial's lead investigator Peter White) to release the trial data to a patient who had requested it, subject to appeal within 28 days. Three Freedom of Information requests from 2012 and 2013 were included in the ICO's decision. An appeal by QMUL was heard by the First-Tier Tribunal on 20-22 April 2016. QMUL responded to a freedom of information request confirming the cost of its legal fees for the tribunal totalled £245,745.27 (around USD350,000). The First-Tier Tribunal judgement was published on 16 August 2016, roundly dismissing the appeal by QMUL, and deciding that the PACE trial data should be released. The university has not yet stated whether it will appeal the judgement.

The PACE patient consent form was released through a Freedom of Information request.

Dr Richard Horton, editor of The Lancet, stated on 18 April 2011 in a national Australian radio interview: "The Freedom of Information requests and the legal fees that have been racked up over the years because of these vexatious claims has added another £750,000 of taxpayers’ money to the conduct of this study".

Data requests from scientists
Professor James Coyne has publicly called for the trial data to be released. He has repeatedly criticized the PACE investigators for failing to abide by modern expectations concerning "open data".

Professor Coyne's own request for the data was dismissed under the Freedom of Information Act by the study authors as "vexatious" and as having an "improper motive".

Scientists Ronald Davis, David Tuller, Bruce Levin, and Vincent Racaniello requested the PACE trial data in December 2015. Their request was rejected by the trial investigators.

Other calls for data release
A number of groups and individuals have called for the release of the PACE data, including some outside the ME/CFS community who advocate "open data" in science. These calls include:


 * 2016: open letters from two patient groups in Australia, calling for the data to be released.
 * 2016: an open letter from patient groups in 14 European countries, calling for the data to be released.
 * 2016: an open letter by Mark Berry of Phoenix Rising calling for the data to be released.
 * 2016: an article, "PACE trial and other clinical data sharing: patient privacy concerns and parasite paranoia", by Leonid Schneider, an independent science journalist.
 * 2016: open letters from British patient charities Action for ME, Invest in ME, ME Association, Tymes Trust, ME Research UK, Hope 4 ME & Fibro NI, the Welsh Association of ME & CFS Support and the 25 Percent ME Group.
 * 2016: an open letter from a Canadian patient group, the National ME/FM Action Network.
 * 2015: a blog post by Professor Andrew Gelman, a statistician at Columbia University, saying "when researchers refuse to share data, and how they came up with it, they lose the right to call what they do science".
 * 2015: a blog post by Dr Richard Smith, former editor of The BMJ, who said that the PACE authors' institutions were "making a mistake... the inevitable conclusion is that they have something to hide.”

Learn more

 * 2016, Tribunal was right to order release of chronic fatigue trial data, Jonathan Edwards, 27 Aug 2016.
 * 2016, Researchers who claimed chronic fatigue is “all in the mind” forced to disclose data
 * 2016, Chronic Fatigue Syndrome sufferers have just had a small victory, iNews UK, 19 Aug 2016.
 * 2016, Chronic Fatigue Syndrome: tribunal orders data from controversial trial to be released, iNews UK, 19 Aug 2016.
 * 2016, Major breakthrough on PACE trial, The Centre for Welfare Reform, 19 Aug 2016.
 * 2016, QMUL "studying" PACE data-release ruling, #MEAction, 17 Aug 2016.
 * 2016, Release the PACE trial data: My submission to the UK Tribunal, James Coyne, 18 Aug 2016.
 * 2016, Tracking retractions as a window into the scientific process UK tribunal orders release of data from controversial chronic fatigue syndrome study, Retraction Watch, 17 Aug 2016.

Release of Data
Alem Matthees

Learn more

 * 2016, Bad science misled millions with chronic fatigue syndrome. Here’s how we fought back, Julie Rehmeyer, Stat News, 21 Sep 2016.

AHRQ amendment
The US government agency called the Agency for Health Research Quality revised its earlier recommendations about found that when studies of CBT and GET, including PACE, that used the Oxford Criteria were excluded, there was no evidence for graded exercise and only weak evidence for CBT.

Vincent Racaniello
Vincent Racaniello is a virologist at Columbia University in New York in the United States.

"'This is a flawed study, it has to be fixed and people are being harmed by it.'"

"'... multiple flaws that are inexcusable.'"

Trevor Butterworth
Trevor Butterworth is the Editor of 'Sense About Statistics', an online collaboration between the American Statistical Association and Sense About Science USA.

"'...the way PACE was designed and redesigned means it cannot provide reliable answers to the questions it asked. There is really not a lot that can be said to mitigate that; it’s a terminal prognosis.'"

Professor James Coyne
Professor Coyne is Professor of Health Psychology, University Medical Center, Groningen and University of the Netherlands; Distinguished Visiting Professor at the Institute for Health Policy, Rutgers, the State University of New Jersey; and Professor Emeritus of Psychology in the Department of Psychiatry, University of Pennsylvania. He is one of the most cited psychologists in the academic literature.

"'The data presented are uninterpretable. We can temporarily suspend critical thinking and some basic rules for conducting randomized trials (RCTs), follow-up studies, and analyzing the subsequent data. Even if we do, we should reject some of the interpretations offered by the PACE investigators as unfairly spun to fit what [is] already a distorted positive interpretation of the results.'"

"'The self-report measures do not necessarily capture subjective experience, only forced choice responses to a limited set of statements.'"

"'One of the two outcome measures, the physical health scale of the SF-36 requires forced choice responses to a limited set of statements selected for general utility across all mental and physical conditions.'"

"'The validity [of the] other primary outcome measure, the Chalder Fatigue Scale depends heavily on research conducted by this investigator group and has inadequate validation of its sensitivity to change in objective measures of functioning.'"

Professor Coyne gave a public talk criticising the PACE trial in Edinburgh in November 2015. Video footage is available , as are a slide show , a full and an edited transcript  and an audio recording.

He spoke again about the PACE study in Belfast in February 2016 where he described it as "a wasteful trainwreck of a study".

Professor Coyne has questioned whether the PACE trial paper could ever have been properly peer-reviewed, given the large number of study authors and the small world of British science.

Professors James Coyne and Keith Laws
Professor Coyne and Professor Laws of the University of Hertfordshire have criticised, in a joint letter to Lancet Psychiatry, the long-term follow-up analysis of the PACE trial that was published in 2015. Referring to the results of the study as a whole, they said:

"'There are no group differences, and the overall mean short-form 36 (SF-63) physical functioning score is less than 60. It is useful to put this number in context. 77% of the PACE trial participants were women, and the mean age of the trial population was 38 years, with no other disabling medical conditions. Patients with lupus have a mean physical functioning score of 63, patients with class II congestive heart failure have a mean score lower than 60, and normal controls with no long-term health problems have a mean score of 93.'"

Professor Ronald Davis
Professor Ronald Davis is a world-famous geneticist at Stanford University, known for work that enabled the Human Genome Project.

"“I’m shocked that the Lancet published it... The PACE study has so many flaws and there are so many questions you’d want to ask about it that I don’t understand how it got through any kind of peer review.”"

Emeritus Professor Jonathan Edwards
Professor Edwards, of University College London, is internationally known for his pioneering work in establishing B-cell depletion therapy as an effective treatment for rheumatoid arthritis.

"“It’s a mass of un-interpretability to me…All the issues with the trial are extremely worrying, making interpretation of the clinical significance of the findings more or less impossible.”"

Professor Rebecca Goldin
Professor Goldin is Professor of Mathematical Sciences at George Mason University and Director of STATS.org (USA).

"'The PACE design changed so significantly as to leave many wondering whether there is value in the study itself.'"

"'It seems that the best we can glean from PACE is that study design is essential to good science, and the flaws in this design were enough to doom its results from the start.'"

Dr Ellen Goudsmit
Dr Goudsmit is a retired health psychologist who has published a number of criticisms of the PACE trial.

"'The PACE trial was scientifically extremely poor'"

"'A treatment like GET is simply not appropriate for a disease like ME which is linked to infection and metabolic abnormalities. Given the close relationship between exertion and symptoms, it follows that asking a patient to increase their activity levels is as logical as advising smokers with lung cancer to gradually increase the number of cigarettes they smoke'"

Professor Leonard Jason
Leonard Jason is a professor of psychology at DePaul University in Chicago, Illinois, and director of its Center for Community Research.

"“The PACE authors should have reduced the kind of blatant methodological lapses that can impugn the credibility of the research, such as having overlapping recovery and entry/disability criteria.”"

Professor Bruce Levin
Professor Levin is a professor of biostatistics at Columbia University and an expert in clinical trial design.

"“To let participants know that interventions have been selected by a government committee ‘based on the best available evidence’ strikes me as the height of clinical trial amateurism.”"

Professor Arthur Reingold
Professor Reingold is Head of Epidemiology at the University of California, Berkeley.

"“Under the circumstances, an independent review of the trial conducted by experts not involved in the design or conduct of the study would seem to be very much in order.”"

Dr. Charles Shepherd
Dr Shepherd, medical advisor to the ME Association, has criticised the trial's long-term follow-up analyses:

"'Without robust objective evidence relating to improvement and recovery, the ME patient community will continue to regard the PACE trial as a tremendous waste of research funding money'."

Dr David Tuller
Dr Tuller is is academic coordinator of the University of California, Berkeley's joint masters program in public health and journalism. He was a reporter and editor for 10 years at the San Francisco Chronicle, served as health editor at Salon.com and frequently writes about health for The New York Times. He has written extensively about the PACE trial.

"'The study included a bizarre paradox: participants’ baseline scores for the two primary outcomes of physical function and fatigue could qualify them simultaneously as disabled enough to get into the trial but already 'recovered' on those indicators–even before any treatment. In fact, 13 percent of the study sample was already 'recovered' on one of these two measures at the start of the study.'"

"'In the middle of the study, the PACE team published a newsletter for participants that included glowing testimonials from earlier trial subjects about how much the 'therapy' and 'treatment' helped them. The newsletter also included an article informing participants that the two interventions pioneered by the investigators and being tested for efficacy in the trial, graded exercise therapy and cognitive behavior therapy, had been recommended as treatments by a U.K. government committee 'based on the best available evidence.' The newsletter article did not mention that a key PACE investigator was also serving on the U.K. government committee that endorsed the PACE therapies.'"

"'The PACE team changed all the methods outlined in its protocol for assessing the primary outcomes of physical function and fatigue, but did not take necessary steps to demonstrate that the revised methods and findings were robust, such as including sensitivity analyses. The researchers also relaxed all four of the criteria outlined in the protocol for defining 'recovery.' They have rejected requests from patients for the findings as originally promised in the protocol as 'vexatious.''"

"'The PACE claims of successful treatment and 'recovery' were based solely on subjective outcomes. All the objective measures from the trial—a walking test, a step test, and data on employment and the receipt of financial information—failed to provide any evidence to support such claims. Afterwards, the PACE authors dismissed their own main objective measures as non-objective, irrelevant, or unreliable.'"

"'In seeking informed consent, the PACE authors violated their own protocol, which included an explicit commitment to tell prospective participants about any possible conflicts of interest. The main investigators have had longstanding financial and consulting ties with disability insurance companies, having advised them for years that cognitive behavior therapy and graded exercise therapy could get claimants off benefits and back to work. Yet prospective participants were not told about any insurance industry links and the information was not included on consent forms. The authors did include the information in the 'conflicts of interest' sections of the published papers.'"

"'The Lancet Psychiatry follow-up had null findings: Two years or more after randomization, there were no differences in reported levels of fatigue and physical function between those assigned to any of the groups... Yet the authors, once again, attempted to spin this mess as a success.'"

"'This study is a piece of crap'"

Dr David Tuller and Julie Rehmeyer
Public health expert Dr Tuller and ME/CFS patient Julie Rehmeyer are both journalists who have written critically about the PACE authors' claims regarding the safety of Graded exercise therapy:

"'The study’s primary case definition for identifying participants, called the Oxford criteria, was extremely broad; it required only six months of medically unexplained fatigue, with no other symptoms necessary. Indeed, 16% of the participants didn’t even have exercise intolerance—now recognized as the primary symptom of ME/CFS'."

"'After the trial began, the researchers tightened their definition of harms, just as they had relaxed their methods of assessing improvement.'"

"'[T]he study was unblinded, so both participants and therapists knew the treatment being administered. Many participants were probably aware that the researchers themselves favored graded exercise therapy and another treatment, cognitive behavior therapy, which also involved increasing activity levels. Such information has been shown in other studies to lead to efforts to cooperate, which in this case could lead to lowered reporting of harms.'"

Julie Rehmeyer
"'... one of the most damaging cases of bad statistical practice that I have personally encountered in my years as a journalist'"

"'... an object lesson in how our systems can break down. In this case there were serious breakdowns statistically, scientifically, journalistically and in public health.'"

Dr Michael VanElzakker
"'Subjective measures of sick people before & after they are repeatedly told 'You're not sick' is a social psych study, not a clinical trial.'"

"'In 5 years, the UK medical establishment's obdurateness on ME/CFS and PACE will be taught in medical schools as a cautionary tale.'"

"'The PACE trial is a classic case of bad science - researchers are determined to support their theory, even if the data do not.'"

Analysis by "citizen-scientists"
Several patients and other interested parties have produced critiques of PACE's statistical analyses and trial methodology.

Robert Courtney
Mr Courtney has written a number of published letters in the medical journals, criticising PACE.

"'Chalder and colleagues acknowledge that the trial outcomes do not support the hypothetical deconditioning model of GET for chronic fatigue syndrome'."

Peter Kemp
Peter Kemp has written a detailed critique of the study.

Angela Kennedy
Angela Kennedy has made specific critiques of PACE regarding the following areas:


 * 1) Serious risks to clinical patient safety caused by unsound claims made about the efficacy of CBT and GET following the PACE trial;
 * 2) Gross discrepancies between research and clinical cohorts, and how clinical patients (and the physiological dysfunction associated with them) appear to have been actively excluded from PACE and other research by the research group involved in PACE, which has, ironically, caused serious resulting risks to clinical patient safety in the UK in particular;
 * 3) Related to the above, gross discrepancies in how various sets of patient criteria were used (and/or rejected), including but not limited to a changing of the London criteria by PACE authors from its original state, a set of criteria which was already controversial and problematic to start with for a number of reasons;
 * 4) Failure of the PACE trial authors to acknowledge the range and depth of scientific literature documenting serious physiological dysfunction in patients given diagnoses of ME or CFS, and how CBT and GET approaches may endanger patients in this context;
 * 5) The inclusion of major mental illnesses in the research cohort;
 * 6) The distortion by PACE trial researchers of 'pacing' from an autonomous flexible management strategy for patients into a therapist led Graded Activity approach;
 * 7) The post hoc dismissal of adverse outcomes as irrelevant to the trial, in direct contradiction to what is scientifically known about the physiological dysfunctions of people given diagnoses of Myalgic Encephalomyelitis or Chronic Fatigue Syndrome;
 * 8) The instability of 'specialist medical care' as a treatment category, and the lack of any sound category of 'control' group.

Tom Kindlon
Mr Kindlon is a patient and Vice-Chairman of the Irish ME Association. He has published extensive criticism of the PACE trial. In 2011 he published a paper on harms associated with Graded exercise therapy.

Graham McPhee and Tom Kindlon
Mr. McPhee and Mr. Kindlon and others have collaborated on a set of explanatory videos about flaws in PACE's statistical analyses:


 * The PACE Race
 * 60 - The new 75
 * Not so bad
 * The force of LOGic

Tom Kindlon has also written a large number of letters and comments that have been published in medical journals in response to the published papers.

Among many other published letters that have been critical of the trial, many are from people who have identified themselves as patients. For example, most of the letters published by The Lancet criticising the 2011 PACE paper were from patients or representatives of patients' groups.

MEAction
MEAction has published an overview of PACE and its flaws, produced by patients.

Frank Twisk
Dutch patient Frank Twisk of the ME-de-patiënten Foundation has also published criticism of the PACE trial.

"'The PACE trial investigated the effects of CBT and GET in chronic fatigue, as defined by the Oxford criteria, not in chronic fatigue syndrome, let alone myalgic encephalomyelitis'."

"'[T]he positive effect of CBT and GET in subjective measures, fatigue and physical functioning, cannot be qualified as sufficient. Mean short form-36 physical functioning scores in the CBT group (62·2) and the GET group (59·8) at follow-up were below the inclusion cutoff score for the PACE trial (≤65)3 and far below the objective for recovery as defined in the PACE protocol (≥85)'."

"'The vast majority of patients improved subjectively by specialist medical care and APT to the same level as by CBT and GET, without any additional therapies, including CBT and GET, or by other therapies'."

"'[L]ooking at subjective outcomes at follow-up and objective outcomes in earlier studies, such as physical fitness, return to employment, social welfare benefits, and health-care usage, CBT and GET, like specialist medical care and APT, cannot be qualified as effective'."

Janelle Wiley and Graham McPhee
Janelle Wiley and Graham McPhee also collaborated with others to create a website summarising their critique of the trial.

Principal investigators and researchers
The principal investigators on the PACE trial are Professors Peter White, Trudie Chalder and Michael Sharpe. Additional authors on the 2011 Lancet paper are Kimberley Goldsmith, Anthony Johnson, Laura Potts, Rebecca Walwyn, Julia DeCesare, Hannah Baber, M. Burgess, L.V. Clark, D.L. Cox, Jessica Bavinton, Brian Angus, Gabrielle Murphy, Maurice Murphy, H. O'Dowd, D. Wilks, and Paul McCrone.

2003: Trial Registry. BioMed Central. ISRCTN54285094
There is a currently published trial register and there is a version of the register that is no longer available on the web but has been archived. Both versions contain slightly different details. The archived version contains the details of the trial's pre-specified endpoint analyses.

2006: Final protocol version 5.0
This full version of the study protocol, which includes trial materials such as questionnaires and consent forms, was never officially published.

2007: PACE trial protocol
BMC Neurology published the trial's planned methodology, including its planned analyses.

2011: Main trial outcomes
The trial's main outcomes, and some selected secondary outcomes, were reported in The Lancet. Forty-four letters were submitted in a response that the journal's editor described as "swift and damning".

2012: Cost-effectiveness of CBT and GET
This paper was published in the PLoS One journal and concluded that cognitive behavioral therapy and graded exercise therapy had the best probability of being the most cost-effective treatments. Controversy has broken out over the failure of the study authors to provide the underlying data to Professor James Coyne under PLoS One's data-sharing policy. Journalist David Tuller has criticized the study's assumptions and conclusions.

2013: "Recovery" rates
This paper appeared in Psychological Medicine. The Science Media Centre issued an "expert opinion" about the study.

ME/CFS patient Graham McPhee and others created a video animation - How's that recovery? - explaining problems with the new analyses that had replaced those specified in the study protocol. Sam Carter applied the new fatigue and physical function recovery criteria to the data from the FINE trial and found that doing so increased the number of "recovered" patients six-fold, compared to the original criteria.

Patient-advocate Peter Kemp also criticized the study, stating that the authors had "twisted the SF-36 Physical Function subscale to suit their needs".

Patients created a tongue-in-cheek song video to satirically criticize the recovery paper results.

2013: Statistical analysis plan
Trials Journal published the detailed plan for PACE's data analysis.

2014: Adverse effects
The Journal of Psychosomatic Research published the results on safety and adverse effects.

2015: Secondary mediation analysis
The Lancet Psychiatry published this paper.

The paper has been criticised by Byron Hyde.



2015: Long-term follow-up
Long-term follow-up results were published in The Lancet Psychiatry in October 2015.

The paper states that at least two years after patients were randomised, "there were no significant differences" in outcomes between the treatment groups. This indicated that APT, CBT and GET added nothing to specialist medical care (SMC), which all groups received. However, the study authors interpreted the results as favouring CBT and GET.

The Science Media Centre published "expert reaction" to the paper.

Professors James Coyne and Keith Laws criticised the results as "uninterpretable" and consisting of "null findings". The ME Association also criticized the follow-up study.

2015: Longitudinal mediation analysis
This short paper published in Trials Journal concluded: "Approximately half of the effect of each of CBT and GET [...] on physical function was mediated through reducing avoidance of fearful situations".

Other publications

 * 2014: Pain in chronic fatigue syndrome: response to rehabilitative treatments in the PACE trial
 * 2013: The planning, implementation and publication of a complex intervention trial for chronic fatigue syndrome: the PACE trial
 * 2013: Cognitions, behaviours and co-morbid psychiatric diagnoses in patients with chronic fatigue syndrome
 * 2013: Training, Supervision & Therapists' Adherence to Manual Based Therapies
 * 2011: Measuring disability in patients with chronic fatigue syndrome: reliability and validity of the Work and Social Adjustment Scale
 * 2010: Psychiatric misdiagnoses in patients with chronic fatigue syndrome

Talks & interviews

 * 2011: Professors Michael Sharpe and Trudie Chalder were videoed  at The Lancet's press conference for the publication of the trial's main results in 2011.
 * 2015: Professor James Coyne gave a talk on "A skeptical look at the PACE chronic fatigue trial" in Edinburgh (with YouTube recording,  transcript, and slides available online) and, more recently, Belfast (with YouTube recording and slides available online
 * 2016: While in Amsterdam at The Forgotten Plague Conference, David Tuller gave an interview with Frank Twisk on 27 Feb 2016. The following day, 28 Feb 2016, David Tuller gave a speech with Q&As.
 * 2011, Michael Sharpe interview

Learn more

 * Wikipedia - Chronic fatigue syndrome treatment
 * Wikipedia - Controversies related to chronic fatigue syndrome
 * 2016, UK tribunal orders release of data from controversial chronic fatigue syndrome study (Retraction Watch)
 * 2016, Major breakthrough on PACE trial (Centre for Welfare Reform)
 * 2016, AHRQ Evidence Review Changes Its Conclusions
 * 2016, Queen Mary and PACE, just what is their case? (Graham McPhee)
 * 2016, Tribunal orders release of PACE trial data (QMUL v the IC and Matthees)
 * 2016, Tribunal orders QMUL to release anonymised PACE data 16 Aug 2016
 * 2016, Tribunal orders release of PACE trial data (James Coyne)
 * 2016, Tribunal orders release of PACE data, #MEAction, 16 Aug 2016
 * 2016, Rehmeyer makes statisticians' "jaws drop" over PACE
 * 2016, Tuller slams terrible PACE in podcast
 * 2016, Over $1m spent fighting PACE Trial data release
 * 2016: PACE: The research that sparked a patient rebellion and challenged medicine, Rebecca Goldin, Sense About Statistics, 21 Mar 2016
 * 2016: Patients, Scientists Fight Over Research-Data Access, Amy Dockser Marcus, Wall Street Journal, 7 Mar 2016
 * 2016: ‘It was like being buried alive’: battle to recover from chronic fatigue syndrome, The Guardian, UK, 15 Feb 2016
 * 2016: PACE trial and other clinical data sharing: patient privacy concerns and parasite paranoia, Leonid Schneider, Feb 2016
 * 2016: Tuller: PACE authors "wrapping themselves in victimhood", David Tuller, 01 Feb 2016
 * 2016: PACE trial's forbidden fruit - is the data really poisonous?, AutoDidact Blog, 25 Jan 2016
 * 2011, ME – the truth about exercise and therapy (Jane Colby)
 * 2011: "Interview with Michael Sharpe and Richard Horton, Radio National, Australia, 18 Apr 2011
 * 2011: Expert Opinion on ME/CFS Study, Science Media Centre, UK, 17 Feb 2011.
 * 2011 Study finds therapy and exercise best for ME, The Guardian, UK, 18 Feb 2011. (author Trudie Chalder stated "twice as many people on graded exercise therapy and cognitive behaviour therapy got back to normal")