Clamour grows for independent inquiry into the PACE Trial | open letter to The Lancet republished | 11 February 2016

February 11, 2016


Three more Brits have added their signatures to an open letter to Dr Richard Horton, editor of The Lancet, calling for an independent inquiry into the PACE Trial. The signatories are all researchers and clinicians from round the world.

Dr Charles Shepherd and Dr Nigel Speight, both medical advisers to the ME Association, and infectious diseases consultant Dr William Weir are now among the 42 signatories who have signed the letter – which first appeared on Dr Vincent Rancaniello's ‘Virology' blog on November 13.

The letter was re-published yesterday – alongside this note from Dr Rancaniello:

“On November 13th, five colleagues and I released an open letter to The Lancet and editor Richard Horton about the PACE trial, which the journal published in 2011. The study’s reported findings – that cognitive behavior therapy and graded exercise therapy are effective treatments for chronic fatigue syndrome – have had enormous influence on clinical guidelines for the illness.

“Last October, Virology Blog published David Tuller’s investigative report on the PACE study’s indefensible methodological lapses. Citing these problems, we noted in the letter that “such flaws have no place in published research” and urged Dr. Horton to commission a fully independent review.

“Although Dr. Horton’s office e-mailed that he would respond to our letter when he returned from “traveling,” it has now been almost three months. Dr. Horton has remained silent on the issue. Today, therefore, we are reposting the open letter and resending it to The Lancet and Dr. Horton, with the names of three dozen more leading scientists and clinicians, most of them well-known experts in the ME/CFS field.

“We still hope and expect that Dr. Horton will address – rather than continue to ignore – these critical concerns about the PACE study.”


TEXT OF THE OPEN LETTER


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

****

Dharam V. Ablashi, DVM, MS, Dip Bact
Scientific Director, HHV-6 Foundation
Former Senior Investigator
National Cancer Institute, NIH
Bethesda, Maryland

James N. Baraniuk, MD
Professor, Department of Medicine,
Georgetown University
Washington, D.C.

Lisa F. Barcellos, PhD, MPH
Professor of Epidemiology
School of Public Health
California Institute for Quantitative Biosciences
University of California
Berkeley, California

Lucinda Bateman, MD
Medical Director, Bateman Horne Center
Salt Lake City, Utah

David S. Bell, MD
Clinical Associate Professor of Pediatrics
State University of New York at Buffalo
Buffalo, New York

Alison C. Bested MD FRCPC
Clinical Associate Professor of Hematology
University of British Columbia
Vancouver, British Columbia, Canada

Gordon Broderick, PhD
Director, Clinical Systems Biology Group
Institute for Neuro Immune Medicine
Professor, Dept of Psychology and Neuroscience
College of Psychology
Nova Southeastern University
Miami, Florida

John Chia, MD
Clinician/Researcher
EV Med Research
Lomita, California

Lily Chu, MD, MSHS
Independent Researcher
San Francisco, California

Derek Enlander, MD, MRCS, LRCP
Attending Physician
Mount Sinai Medical Center, New York
ME CFS Center, Mount Sinai School of Medicine
New York, New York

Mary Ann Fletcher, PhD
Schemel Professor of Neuroimmune Medicine
College of Osteopathic Medicine
Nova Southeastern University
Professor Emeritus, University of Miami School of Medicine
Fort Lauderdale, Florida

Kenneth Friedman, PhD
Associate Professor of Pharmacology and Physiology (retired)
New Jersey Medical School
University of Medicine and Dentistry of NJ
Newark, New Jersey

David L. Kaufman, MD,
Medical Director
Open Medicine Institute
Mountain View, California

Nancy Klimas, MD
Professor and Chair, Department of Clinical Immunology
Director, Institute for Neuro-Immune Medicine
Nova Southeastern University
Director, GWI and ME/CFS Research, Miami VA Medical Center
Miami, Florida

Charles W. Lapp, MD
Director, Hunter-Hopkins Center
Assistant Consulting Professor at Duke University Medical Center
Charlotte, North Carolina

Susan Levine, MD
Clinician, Private Practice
New York, New York
Visiting Fellow, Cornell University
Ithaca, New York

Alan R. Light, PhD
Professor, Department of Anesthesiology and Department of Neurobiology and Anatomy
University of Utah
Salt Lake City, Utah

Sonya Marshall-Gradisnik, PhD
Professor and Co-Director
National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Queensland, Australia

Peter G. Medveczky, MD
Professor, Department of Molecular Medicine, MDC 7
College of Medicine
University of South Florida
Tampa, Florida

Zaher Nahle, PhD, MPA
Vice President for Research and Scientific Programs
Solve ME/CFS Initiative
Los Angeles, California

James M. Oleske, MD, MPH
Francois-Xavier Bagnoud Professor of Pediatrics
Senator of RBHS Research Centers, Bureaus, and Institutes
Director, Division of Pediatrics Allergy, Immunology & Infectious Diseases
Department of Pediatrics
Rutgers – New Jersey Medical School
Newark, New Jersey

Richard N. Podell, M.D., MPH
Clinical Professor
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey

Charles Shepherd, MB, BS
Honorary Medical Adviser to the ME Association
London, United Kingdom

Christopher R. Snell, PhD
Scientific Director
WorkWell Foundation
Ripon, California

Nigel Speight, MA, MB, BChir, FRCP, FRCPCH, DCH
Pediatrician
County Durham, United Kingdom

Donald Staines, MBBS MPH FAFPHM FAFOEM
Professor and Co-Director
National Centre for Neuroimmunology and Emerging Diseases
Griffith University
Queensland, Australia

Philip B. Stark, PhD
Professor of Statistics
University of California, Berkeley
Berkeley, California

Eleanor Stein, MD FRCP(C)
Assistant Clinical Professor
University of Calgary
Calgary, Alberta, Canada

John Swartzberg, MD
Clinical Professor Emeritus
School of Public Health
University of California, Berkeley
Berkeley, California

Ronald G. Tompkins, MD, ScD
Summer M Redstone Professor of Surgery
Harvard University
Boston, Massachusetts

Rosemary Underhill, MB BS.
Physician, Independent Researcher
Palm Coast, Florida

Dr Rosamund Vallings MNZM, MB BS
General Practitioner
Auckland, New Zealand

Michael VanElzakker, PhD
Research Fellow, Psychiatric Neuroscience Division
Harvard Medical School & Massachusetts General Hospital
Boston, Massachusetts

William Weir, FRCP
Infectious Disease Consultant
London, England

Marcie Zinn, PhD
Research Consultant in Experimental Neuropsychology, qEEG/LORETA, Medical/Psychological Statistics
NeuroCognitive Research Institute, Chicago
Center for Community Research
DePaul University
Chicago, Illinois

Mark Zinn, MM
Research consultant in experimental electrophysiology
Center for Community Research
DePaul University
Chicago, Illinois

8 thoughts on “Clamour grows for independent inquiry into the PACE Trial | open letter to The Lancet republished | 11 February 2016”

  1. I’m so glad and grateful to all these scientists with high academic standing for keeping up the momentum on getting the wretched data released. It’s very good to see our three UK names alongside; I hope many other UK medics and scientists will add their voices too. No excuse for sitting on the fence – take note, AfME!

    1. Sorry – four not three UK voices; Prof. Jonathon Edwards of UCL was, of course, one of the original signatories.

  2. Excellent. What a wonderful group of names below the letter, it looks like a who’s who of real work on ME/CFS. Good to see Dr Shepherd and Dr Speight in the list.

    Were AfME given the chance to add a signatory?

    Dr Horton hasn’t replied in 3 months? I do have the feeling he is a bit too involved with the psychiatrists.

  3. Thank you so much to all the incredible Doctors and Researchers including our very own 3 UK Doctors who have signed this letter. I and thousands like me have been waiting for this moment for so many years.

    I hope many more of our own Doctors will now feel able to join the signatories and back this call for the release of the PACE Data.

    3 months is too long Dr Horton.

  4. Nice work. The list of signatories at the end is starting to look like an impressive line up. To an outside or casual bystander, it would seem that medical research in the UK has, until now at least, relied upon what looks like a ‘gentleman’s code of honour’ between doctors, scientists, publishing groups & the public, under which it is assumed that the research and publication process is undertaken with integrity. It appears to have failed on this occasion.

  5. CBT/GET rationale goes like this. it overlaps with the other headologies such as Lightning and Gupta, though with different emphases and methodologies (sometimes contrasting, esp between LP and CBT/GET)
    CBT/GET will help to a degree if:
    1) There is deconditiong which can be plausibly attributed to inactivity. Patient attitude to this attribution may be crucial.
    2) There is a neurotic/hysterical attitude of fear of symptoms and of activity as a potential precipitator of symptoms. This will cause/exacerbate avoidance and may contribute to stress related somatic symptoms. This attitude must be challenged.
    1) AND 2) CAN BE TERMED “NEUROTIC/HYSTERICAL DECONDITIONING”.
    3) There is biological entrainment of inactivity. It becomes “endogenised” altering numerous physiological paramaters (the transisition from exogenous to endogenised antidepressant responsive depression may serve as an analogy).
    4) There may be psychological associations such that if the patient was bedbound in the early infective state of the illness, the same symptoms will be experienced by the patient remaining in that setting, thus a pattern of inactivity will contribute to a pattern of symptoms through psychological mechanisms. Similarly if excessive physical exertion was implicated in early infective phase illness, too sudden return to full activity, appropriate to a healthy person, may also precipitate symptoms. Thus GRADED activity/exercise is needed. (Contrast here with LP)
    5) following on 4) it is worth considering that physiological and functional parameters can respond to environment in otherwise healthy persons, e.g. the aging, whose functional markers of aging can improve in settings reminiscent of their youth, whcih reinforce positive, healthful internal attitudes and emotions. Altering behaviours and thus immediate external environment should be accomplished as per points above AND alongside alteration of thought and attitudinal patterns in the patient’s internal environment towards empowerment , optimism etc.

    THIS IS ALL VERY WELL FOR THOSE WHO FIT THE ABOVE PICTURE. IT PRETTY MUCH DEFINES A CERTAIN SET OF PATIENTS AS POTENTIAL RESPONDERS. BUT,HOW ARE THEY CHOSEN? IN SHORT HOW IS EXCLUSION DIAGNOSIS CONDUCTED, SO AS TO DIRECT ONLY THOSE PATIENTS TO CBT/GET WHO MIGHT BENEFIT? AND WHAT DO THE OTHERS DO?
    FOR THOSE WHO PARTIALLY FIT, IS MORE POSITIVE ATTITUDE NECESSARY OR MORE BIOPHYSICAL MEDICINE? WHAT BIOPHYSICAL MEDICINE IS NICE RECOMMENDING?
    WHAT IS THE RESPONSE OF THE LANCET TO THE PLETHORA OF BIOPHYSICAL RESEARCH SHOWING PHYSIOLOGICAL ABRNORMALITIES WHICH ARE NOT USUALLY EXPLAINED BY DECONDITIONING/NEUROSIS?
    IF THOSE PATIENTS WHO DO NOT FIT ARE IN THE WORDS OF ONE LEADING “EXPERT” TO “GO SOMEWHERE ELSE” TO WHOM IN THE NHS SHOULD WE GO?
    CRUCIALLY WHAT ARE HORTON’S BELIEFS?
    DOES HORTON HIMSELF BELIEVE WE HAVE PHYSICAL DECONDITIONING OR IS IN IN HIS OWN VIEW NEUROTIC DECONDITIONING? IS THIS WHY WE SHOULD SEE A PSYCHIATRIST!!!! FOR DECONDITIONING?
    DOES HORTON HIMSELF BELIEVE THAT WE REALLY HAVE A FALSE ILLNESS BELIEF OR IF NOT A ONE OF FALSE BELIEF, NEVERTHELESS A “FALSE ILLNESS STATE”, ALBEIT AN ENTRAINED AND THEREFORE “REAL” ONE? BECAUSE IF HE DOES, ONE WONDERS IF HE CARES ABOUT IRREGULARITIES IN SCIENTIFIC PROCEDURE? AFTER ALL WHY SHOULD SCIENTIFIC PROCEDURE BE ADHERED TO IF THE MAIN OBJECT IS TO CONVINCE THE AFFLICTED THAT THEY ARE NOT REALLY CLASSICALLY PHYSICALLY ILL AND THAT THEY SHOULD HENCEFORTH BEHAVE WELL TO GET WELL, WITH BELIEF IN THE THERAPY PLAYING A MAJOR PART IN THE THERAPY ?
    DOES HORTON HIMSELF BELIEVE THAT WE ARE REALLY NEUROTIC, HYSTERICAL, AND WITH LIVES FULL OF NEGATIVE CUES WHICH WE ASSOCIATE WITH ILLNESS, ALL OF WHICH HAVE TOGETHER CREATED A STRESS, PSYCHO-ENVIRONMENTALLY AND MENTALLY INDUCED “FUNCTIONAL” CONDITION, WITH LITTLE BIOPHYSICAL INPUT AT ALL?
    BECAUSE IF HORTON BELIEVES AL THIS HE MAY WELL BELIEVE THAT SUCH PATIENTS ARE NOT SERVED BY SCIENCE BUT BY CONVINCEMENT OF SOME ALLEGEDLY CREDIBLE AND THERAPEUTIC “TRUTH” (MORE IMPORTANT FOR IT TO BE CREDIBLE THAN TRUE) THIS WILL BY PLACEBO ROUSE THE AFFLICTED FROM THEIR NOCEBO BED. THAT IS THE AIM AND, WITH THIS MINDSET, ANY IRREGULARITIES IN SCIENTIFIC PROCEDURE ARE , FOR THE PATIENTS’ SAKES, PERMISSIBLE.

    INFACT, IN PRESENTING THE PACE TRIAL THE LANCET IS GIVING OVER ITS PAGES NOT TO BAD SCIENCE ABOUT A THERAPY, BUT TO A CENTRAL ELEMENT OF THE THERAPY ITSELF.I.E. TO CONVINCING ALL THAT THE THERAPY IS EFFECTIVE IN ORDER FOR IT TO BECOME MORE EFFECTIVE IN PRACTICE.

    THE AIM IS NOT THE WRITING OF SCIENCE BUT THE ONGOING CREATION BY REPEATED ASSERTION OF A THERAPEUTIC ENVIRONMENT OF POSITIVE ATTITUDE TO CBT/GET TO MAKE IT EASIER TO TREAT THE NEUROTICALLY DECONDITIONED AND IN THE HOPE THAT ANY PLACEBO RESPONDERS MIGHT BE HELPED TOO.

    PACE IS NOT SCIENCE, WAS IT EVER MEANT TO BE?

    IF HORTON BUYS INTO THE CBT/GET ANALYSIS THERE WILL BE LITTLE POINT IN ADDRESSING HIM. AS A DOCTOR HE PRESUMABLY WANTS TO MAKE PEOPLE WELL. RATIONALLY AND IN GOOD CONSCIENCE HE CAN ASSERT THAT SCIENCE IS NOT NEEDED FOR A NON SCIENTIFIC ILLNESS AND THAT THOUGH IRREGULAR, TO GIVE OVER PAGES TO ASSISTING A THERAPEUTIC PROCESS IS IN THIS CASE JUSTIFIED (WHILE PRETENDING IT IS SOLID SCIENCE, AS THAT IS HOW THE THERAPEUTIC PROPAGANDA WORKS).

  6. Thank you for this long explanation, but what makes people ill and further damaged is simply wrong.

    My rule of thumb is, if it doesn’t work either blame the patient or exclude them from the data, indicates a complete lack of responsibility and makes me suspicious.

    Many were excluded and many more could not complete the CBT/GET and were then left to their own devices. Many more were included in ME/CFS data who were already ‘recovered’ before the trial and many more didn’t have ME.

    Lightening Process was advertising false information about recovery and Dr Shepherd made sure that was stopped

    That seems to determine therapies in ME and therapies which are falsely advertised by those trying to make money at the expense of the vulnerable, sick and disabled who, when unable to have real help, will clutch at anything.

    For a fuller explanation David Tuller has a volume of critical criteria missing from PACE and with a responsible editor/Doctor all research evidence should have been analysed, before publication in such an important journal which influenced treatment around the world.

    Many trials were showing this to be a neurological illness and the World Health Organisation (WHO) classed it as such, yet none were considered seriously.

    We all want to know what Dr Horton thinks in his much awaited reply.

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