1. Response to The Times report by Professor Fiona Watt Executive chairwoman, Medical Research Council

The Times, Letters to the Editor, August 27, 2018.

Chronic Fatigue

Sir,

Further to your report “Call for review of ‘flawed’ ME research” (Aug 21), as funders of the Pace trial we reject the view that the scientific evidence provided by the trial for using cognitive behavioural theory and managed exercise in the treatment of chronic fatigue syndrome (also known as ME) was unsound.

The Pace trial was funded following expert peer review, was overseen by an independent steering committee, and its published findings have also been independently peer-reviewed. Other research groups have drawn similar conclusions.

Chronic fatigue syndrome/ME remains a priority for the Medical Research Council (MRC), and it is important that researchers are not discouraged from working on the disease because of concerns that they could be subject to the level of hostility that Pace researchers have experienced.

Medical research can only flourish when there is mutual respect between all parties.

Professor Fiona Watt

Executive chairwoman, Medical Research Council

More information:-

A debate on this development has taken place over on Science 4 ME forums where they are hoping to draft a response

Prof. Jonathan Edwards exchanged correspondence with Prof. Fiona Watt from the MRC over the PACE trial during the summer and has placed his letter in the public domain

2. Original article in The Times

Tom Whipple, Science Editor, The Times, August 21, 2018.

More than a hundred academics have joined ten MPs and scores of patient groups from around the world to sign an open letter calling for The Lancet to reanalyse a study into treatment for myalgic encephalomyelitis (ME).

The letter follows a debate in parliament in which one MP said that the study, which is used to set NHS guidelines, “will go down as one of the biggest medical scandals of the 21st century”.

The authors of the research paper stood by their findings and said that the letter represented a campaign to discredit solid research and force the retraction of papers simply because patients disagreed with their findings.

The signatories, who include academics from Harvard, Stanford, UCL and the London School of Hygiene and Tropical Medicine, said that the 2011 Pace trial, which recommended therapy and exercise as a treatment for the condition, had “major flaws” and “unacceptable methodological lapses”.

The £5 million publicly funded trial was published in The Lancet and has informed advice on treating people with ME in the NHS and abroad, but is controversial among ME sufferers. Some claim that its advice perpetuates an idea that the disease, which causes debilitating disability, is all in the mind. The Lancet declined to comment.

3. The open letter to the Lancet re: The PACE trial

Virology Blog:

Trial By Error: Open Letter to The Lancet, version 3.0

David Tuller, 13 August 2018

Two months ago, Professor Racaniello sent Lancet editor Richard Horton an open letter about the indisputable methodological and ethical failings of the PACE trial. This was a follow-up to Virology Blog’s 2016 open letter to Dr. Horton; the new one detailed what has happened since then. Last month, I re-sent and reposted this new open letter, with organizations also signed on. Given Dr Horton’s persistent defense of a study in which 13 % of the participants had already met a key outcome threshold at baseline, it is not surprising that he has failed to respond.

Yesterday I sent the letter to The Lancet for the third time, with more individual experts and organizations adding their voices to the demand for a reassessment of the reported PACE findings. For reasons only Dr Horton can explain, he appears determined to undermine his journal’s reputation for scientific integrity with his robust support for a trial that objective observers clearly recognize as a piece of crap. PACE has caused great harm to the patient community. Dr Horton’s refusal to take appropriate corrective action has amplified that harm many times over. He and his journal have a lot to answer for.

Dear Dr. Horton:

In February, 2011, The Lancet published an article called “Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomized trial.” [1] The article reported that two rehabilitative approaches, cognitive behavioural therapy (CBT) and graded exercise therapy (GET), were effective and safe treatments for chronic fatigue syndrome, also often referred to as myalgic encephalomyelitis, ME/CFS and CFS/ME. The PACE study received international attention and has had widespread influence on research, treatments prescribed for patients, and attitudes toward the illness of both the medical community and the public at large.

At the press conference promoting the Lancet paper, one of the lead investigators stated that twice as many participants in the treatment groups got “back to normal,” compared to those in the other study arms. [2] An accompanying Lancet commentary similarly claimed that these “back-to-normal” participants had met a “strict criterion for recovery.” [3]

In fact, we now know that 13 % of the participants qualified at baseline as “recovered” or “within the normal range” for one of the study’s two primary measures, self-reported physical function–even as they were simultaneously classified as disabled enough on the same measure to enter the study. [4] This anomaly, which occurred because the investigators weakened key outcome thresholds after data collection, invalidates any claims that patients “recovered” or got “back to normal.” The overlap in entry and outcome criteria is only one of the trial’s unacceptable methodological lapses.

The treatments investigated in the PACE trial were based on the hypothesis that ME/CFS patients harbor “unhelpful” convictions about having an ongoing organic disease and that the perpetuation of their devastating symptoms is the result of deconditioning. In contrast, a 2015 review from the U.S. Institute of Medicine (now the National Academy of Medicine), reported that ME/CFS is a complex, multi-system illness characterized by neurological, immunological, autonomic, and energy metabolism dysfunctions. [5] The cardinal symptom, noted the review, is a systemic intolerance to exertion; if patients exceed their available energy resources, they can suffer serious and prolonged relapses.

After The Lancet published the first PACE results, ME/CFS patients and advocates immediately pointed out major flaws. But few people outside the field took notice until the science site Virology Blog published a 15,000-word investigation by David Tuller, a public health researcher and journalist at the University of California, Berkeley, in October of 2015. [6] Subsequently, in February of 2016, many of us signed an open letter to The Lancet requesting an independent investigation of the study. [7]

Since then, much has happened:

* In August of 2016, a U.K. tribunal, citing that open letter, ordered Queen Mary University of London to release raw trial data from the PACE study, sought by Australian patient Alem Matthees in a freedom of information request so that he and others could calculate the outcomes promised in the PACE trial protocol. [8]

* Analyses of these data [9], including a study published in BMC Psychology in March [10], have confirmed what has long been argued: The PACE investigators engaged in such extensive outcome-switching that they were able to report dramatically better findings than the null or minimal results obtained under the original measures they promised in their protocol.

* The U.S. Agency for Healthcare Research and Quality (AHRQ) downgraded its recommendations for CBT and GET. [11] This downgrading occurred after the agency removed from its analysis the PACE trial and other studies using overly broad selection criteria that generated cohorts of patients with a grab-bag of fatiguing conditions. And while the PACE trial claimed that GET is safe, AHRQ found that the therapy was associated with more adverse events.

* Last summer, the U.S. Centers for Disease Control abandoned the recommendations that ME/CFS patients be treated with CBT and GET [12], having already removed references to the PACE trial. A couple of months later, the U.K. National Institute for Health and Care Excellence announced that it would pursue a full update of its 2007 guidance, citing concerns about the reliability and validity of the evidence base. [13]

* Earlier this year, a report from the Dutch Health Council recommended that GET should not be used in the Netherlands as a treatment for the illness. [14]

* In March, a group of leading American clinicians who specialize in ME/CFS unanimously agreed that the two PACE treatments are inappropriate and possibly harmful for patients with the illness and should therefore not be prescribed. [15]

Given the worldwide impact of PACE, we urge The Lancet to do what the open letter two years ago requested: commission an independent re-analysis of the individual-level trial data, with appropriate sensitivity analyses, from highly respected reviewers with extensive expertise in statistics and study design. The reviewers should be from outside the domains of psychiatry and psychological medicine and predominantly from outside the U.K. They should also be completely independent of, and have no conflicts of interests involving, the PACE investigators and the funders of the trial.

Thank you for your quick attention to this matter.

Sincerely,

For the full list of signatories please refer to virology blog. Dr Charles Shepherd and Dr Nigel Speight, medical advisers to the ME Association, together with the Countess of Mar, representing Forward ME, also signed the letter.

The UK Members of Parliament who signed were as follows:

Sir Edward Davey MP

Kingston and Surbiton, England, UK

David Drew MP

Stroud, England, UK

Patricia Gibson MP

North Ayrshire and Arran, Scotland, UK

Mary Glindon MP

North Tyneside, England, UK

Sandy Martin MP

Ipswich, England, UK

Carol Monaghan MP

Glasgow North West, Scotland, UK

Nicky Morgan MP

Loughborough, England, UK

Alex Sobel MP

Leeds North West, England, UK

Graham Stringer MP

Blackley and Broughton, England, UK

Stephen Timms MP

East Ham, England, UK