Six researchers urge the Lancet to accept independent investigation into the PACE Trial | 14 November 2015

November 14, 2015


Six eminent researchers – five from the USA, one from Britain – have signed an open letter which was sent yesterday to the Editor of the Lancet urging the appointment of an independent panel of researchers to investigate what they say are “major flaws” in the way in which the trial outcomes were reported in his journal in 2011.

The signatories include Jonathan Edwards, an Emeritus Professor at University College London. They say the faults mainly concern the recovery claims made within the published study.

“Such flaws have no place in published research. This is of particular concern in the case of the PACE trial because of its significant impact on government policy, public health practice, clinical care, and decisions about disability insurance and other social benefits. Under the circumstances, it is incumbent upon The Lancet to address this matter as soon as possible.”

The open letter was published in ‘Virology Blog' by its founder, Professor Vincent Rancaniello – who is one of the letter signatories. A few days ago, the blog hosted a three-part investigation into the PACE Trial by the American investigative journalist and academic, David Tuller.

The Editor of the Lancet, Dr Richard Horton, has yet to publish his response.


TEXT OF THE LETTER SENT TO THE LANCET


Dr. Richard Horton
The Lancet
125 London Wall
London, EC2Y 5AS, UK

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.” The article reported that two “rehabilitative” approaches, cognitive behavior therapy and graded exercise therapy, were effective in treating chronic fatigue syndrome, also known as myalgic encephalomyelitis, ME/CFS and CFS/ME. The study received international attention and has had widespread influence on research, treatment options and public attitudes.

The PACE study was an unblinded clinical trial with subjective primary outcomes, a design that requires strict vigilance in order to prevent the possibility of bias. Yet the study suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings. The patient and advocacy communities have known this for years, but a recent in-depth report on this site, which included statements from five of us, has brought the extent of the problems to the attention of a broader public. The PACE investigators have replied to many of the criticisms, but their responses have not addressed or answered key concerns.

The major flaws documented at length in the recent report include, but are not limited to, the following:

*The Lancet paper included an analysis in which the outcome thresholds for being “within the normal range” on the two primary measures of fatigue and physical function demonstrated worse health than the criteria for entry, which already indicated serious disability. In fact, 13 percent of the study participants were already “within the normal range” on one or both outcome measures at baseline, but the investigators did not disclose this salient fact in the Lancet paper. In an accompanying Lancet commentary, colleagues of the PACE team defined participants who met these expansive “normal ranges” as having achieved a “strict criterion for recovery.” The PACE authors reviewed this commentary before publication.

*During the trial, the authors published a newsletter for participants that included positive testimonials from earlier participants about the benefits of the “therapy” and “treatment.” The same newsletter included an article that cited the two rehabilitative interventions pioneered by the researchers and being tested in the PACE trial as having been recommended by a U.K. clinical guidelines committee “based on the best available evidence.” The newsletter did not mention that a key PACE investigator also served on the clinical guidelines committee. At the time of the newsletter, two hundred or more participants—about a third of the total sample–were still undergoing assessments.

*Mid-trial, the PACE investigators changed their protocol methods of assessing their primary outcome measures of fatigue and physical function. This is 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.

*The PACE investigators based their claims of treatment success solely on their subjective outcomes. In the Lancet paper, the results of a six-minute walking test—described in the protocol as “an objective measure of physical capacity”–did not support such claims, notwithstanding the minimal gains in one arm. In subsequent comments in another journal, the investigators dismissed the walking-test results as irrelevant, non-objective and fraught with limitations. All the other objective measures in PACE, presented in other journals, also failed. The results of one objective measure, the fitness step-test, were provided in a 2015 paper in The Lancet Psychiatry, but only in the form of a tiny graph. A request for the step-test data used to create the graph was rejected as “vexatious.”

*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.

Such flaws have no place in published research. This is of particular concern in the case of the PACE trial because of its significant impact on government policy, public health practice, clinical care, and decisions about disability insurance and other social benefits. Under the circumstances, it is incumbent upon The Lancet to address this matter as soon as possible.

We therefore urge The Lancet to seek an independent re-analysis of the individual-level PACE 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 U.K. and outside the domains of psychiatry and psychological medicine. 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 very much for your quick attention to this matter.

Sincerely,

Ronald W. Davis, PhD
Professor of Biochemistry and Genetics
Stanford University

Jonathan C.W. Edwards, MD
Emeritus Professor of Medicine
University College London

Leonard A. Jason, PhD
Professor of Psychology
DePaul University

Bruce Levin, PhD
Professor of Biostatistics
Columbia University

Vincent R. Racaniello, PhD
Professor of Microbiology and Immunology
Columbia University

Arthur L. Reingold, MD
Professor of Epidemiology
University of California, Berkeley

8 thoughts on “Six researchers urge the Lancet to accept independent investigation into the PACE Trial | 14 November 2015”

  1. Thank you so much for this article and thank you to all the Doctors who have challenged the PACE Trial results, claims and the Lancet publication of inaccurate, seriously flawed data.

    I pray that now Dr Horton will make the correct decision to think again, apologise for the publication of inaccurate information and make sure future publications include scientifically correct trials of a biological nature with regard to ME/CFS.

  2. I can’t find the words to express what I feel after reading Malcolm Hooper’s report. It highlights the depth to which these people will stoop to keep ME Sufferers down.
    It also explains why so many of our ME Experts and all those who know we have a Neuro immune Disease have been unable to help us knowing the lengths to which their opposition will go to stop them.

    Truly shocking to the core!

  3. Many thanks to the doctors challenging these results. All of us, scientists included, need to be able to have faith in the integrity of published research.

    PACE researchers and the peer review panel at Lancet Psychiatry might also consider the following study findings published this year (2015) in Jacob’s Journal of Physiology.

    They outline the damaging effect of exercise in ME patients, using actual scientific measurements(!). This is perhaps one of the best rebuttals to the PACE trial findings yet.

    Hopefully it can also be widely circulated to all medical journalists in the mainstream press:

    http://www.jacobspublishers.com/images/Physiology/J_J_Physiology_1_2_007.pdf

  4. Thank you Jackie for this link. Skim reading alone has shown me that this is a substantial report with the backing of many eminent doctors previous findings.

    Lets hope that the Lancet and any other media outlet thinking of publishing glowing articles about CBT and GET read this first and think again!!

    Time the PACE Trial was put through independent exorcise trial!!

  5. Another medical hero, the feisty Prof James Coyne, has shared his slide presentation of last night’s Edinburgh pub talk. Links here for anyone who doesn’t “do” Twitter (which is undoubtedly the fastest way to keep up to date with developments and information, but for many of us, another potential brain-overload….very frustrating! but you can still learn a lot simply by looking at peoples’ timelines, and the current hashtags, just not be able to actually join the conversation.)

    Really, hats off, enormous thanks to all these eminent scientists who are standing up for people with ME, challenging the appalling status quo which has prevailed for so very long in this country, unchallenged by a mainstream media hand in glove with those hell-bent in pushing the CBT/GET narrative.
    Prof Coyne has quoted Connie St Louis, Director of the MA in Science Journalism at City University, London, award-winning broadcaster, journalist, writer and scientist, as saying:
    “I would close down the Science Media Centre”. Good! Let’s hope that’s next to go when the PACE “trial” is finally kicked into the long grass.

    http://www.slideshare.net/jamesccoyne/edinburgh-skeptics-in-the-pub-talk-on-pace-chronic-fatigue-trial

    https://twitter.com/hashtag/PubPACE?src=hash

    https://twitter.com/coyneoftherealm

    https://twitter.com/connie_stlouis?lang=en-gb

  6. Brilliant and blood- boiling new article by David Tuller – give him a medal – on the whole can of worms that is the PACE investigators links to the private insurance industry:

    http://www.virology.ws/2015/11/17/trial-by-error-continued-pace-teams-work-for-insurance-companies-not-related-to-pace-really/

    And a Guardian letter from Black Triangle, 2002, showing the links of such warped policies with DWP:

    http://www.theguardian.com/society/2012/sep/12/private-firms-disability-assessment-regime

  7. Thank you Findlow for the links. It’ll take some time to go through but I agree that taking a look into Facebook and Twitter can provide very useful views from a broader perspective.

    It seems the next few weeks and months will be extremely interesting and promising for ME
    I ( Ihope )!!

    Back to reading up for a short while at a time.

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