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An open letter to Psychological Medicine, again!

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Last week, Virology Blog posted an open letter to the editors of Psychological Medicine. The letter called on them to retract the misleading findings that participants in the PACE trial for ME/CFS had “recovered” from cognitive behavior therapy and graded exercise therapy. More than 100 scientists, clinicians, other experts and patient organizations signed the letter.

Three days later, I received a response from Sir Robin Murray, the UK editor of Psychological Medicine. Here’s what he wrote:

 Thank you for your letter and your continuing interest in the paper on the PACE Trial which Psychological Medicine published. I was interested to learn that Wilshire and colleagues have now published a reanalysis of the original data from the PACE Trial in the journal Fatigue: Biomedicine, Health & Behavior, a publication that I was not previously aware of. Presumably, interested parties will now be able to read this reanalysis and compare the scientific qualiity of the re-analysis with that of the original. My understanding is that this is the way that science advances.

This is an unacceptable response.  Sir Robin Murray is misguided if he believes that science advances by allowing misleading claims based on manipulated data to stand in the literature. When researchers include participants who were already “recovered” on key indicators at baseline, the findings are by definition so flawed and nonsensical they must be retracted.

That the editors of Psychological Medicine do not grasp that it is impossible to be “disabled” and “recovered” simultaneously on an outcome measure is astonishing and deeply troubling. It is equally astonishing that the PACE authors now defend themselves, as noted in a New York Times opinion piece on Sunday, by arguing that this overlap doesn’t matter because there were also other recovery criteria.

In response to the comments from Psychological Medicine, we are reposting the open letter with 17 added individuals and 24 more organizations, for a total of 142 signatories altogether. These include two lawyers from Queen Mary University of London, the academic home of lead PACE investigator Peter White, along with other experts and ME/CFS patient groups from around the world.

 

Sir Robin Murray and Dr. Kenneth Kendler
Psychological Medicine
Cambridge University Press
University Printing House
Shaftesbury Road
Cambridge CB2 8BS
UK

Dear Sir Robin Murray and Dr. Kendler:

In 2013, Psychological Medicine published an article called “Recovery from chronic fatigue syndrome after treatments given in the PACE trial.”[1] In the paper, White et al. reported that graded exercise therapy (GET) and cognitive behavioural therapy (CBT) each led to recovery in 22% of patients, compared with only 7% in a comparison group. The two treatments, they concluded, offered patients “the best chance of recovery.”

PACE was the largest clinical trial ever conducted for chronic fatigue syndrome (also known as myalgic encephalomyelitis, or ME/CFS), with the first results published in The Lancet in 2011.[2] It was an open-label study with subjective primary outcomes, a design that requires strict vigilance to prevent the possibility of bias. Yet PACE suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings.[3] Despite these flaws, White et al.’s claims of recovery in Psychological Medicine have greatly impacted treatment, research, and public attitudes towards ME/CFS.

According to the protocol for the PACE trial, participants needed to meet specific benchmarks on four different measures in order to be defined as having achieved “recovery.”[4] But in Psychological Medicine, White et al. significantly relaxed each of the four required outcomes, making “recovery” far easier to achieve. No PACE oversight committees appear to have approved the redefinition of recovery; at least, no such approvals were mentioned. White et al. did not publish the results they would have gotten using the original protocol approach, nor did they include sensitivity analyses, the standard statistical method for assessing the impact of such changes.

Patients, advocates and some scientists quickly pointed out these and other problems. In October of 2015, Virology Blog published an investigation of PACE, by David Tuller of the University of California, Berkeley, that confirmed the trial’s methodological lapses.[5] Since then, more than 12,000 patients and supporters have signed a petition calling for Psychological Medicine to retract the questionable recovery claims. Yet the journal has taken no steps to address the issues.

Last summer, Queen Mary University of London released anonymized PACE trial data under a tribunal order arising from a patient’s freedom-of-information request. In December, an independent research group used that newly released data to calculate the recovery results per the original methodology outlined in the protocol.[6] This reanalysis documented what was already clear: that the claims of recovery could not be taken at face value.

In the reanalysis, which appeared in the journal Fatigue: Biomedicine, Health & Behavior, Wilshire et al. reported that the PACE protocol’s definition of “recovery” yielded recovery rates of 7 % or less for all arms of the trial. Moreover, in contrast to the findings reported in Psychological Medicine, the PACE interventions offered no statistically significant benefits. In conclusion, noted Wilshire et al., “the claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.”

In short, the PACE trial had null results for recovery, according to the protocol definition selected by the authors themselves. Besides the inflated recovery results reported in Psychological Medicine, the study suffered from a host of other problems, including the following:

*In a paradox, the revised recovery thresholds for physical function and fatigue–two of the four recovery measures–were so lax that patients could deteriorate during the trial and yet be counted as “recovered” on these outcomes. In fact, 13 % of participants met one or both of these recovery thresholds at baseline. White et al. did not disclose these salient facts in Psychological Medicine. We know of no other studies in the clinical trial literature in which recovery thresholds for an indicator actually represented worse health status than the entry thresholds for serious disability on the same indicator.

*During the trial, the authors published a newsletter for participants that included glowing testimonials from earlier participants about their positive outcomes in the trial.[7] An article in the same newsletter reported that a national clinical guidelines committee had already recommended CBT and GET as effective; the newsletter article did not mention adaptive pacing therapy, an intervention developed specifically for the PACE trial. The participant testimonials and the newsletter article could have biased the responses of an unknown number of the two hundred or more people still undergoing assessments—about a third of the total sample.

*The PACE protocol included a promise that the investigators would inform prospective participants of “any possible conflicts of interest.” Key PACE investigators have had longstanding relationships with major insurance companies, advising them on how to handle disability claims related to ME/CFS. However, the trial’s consent forms did not mention these self-evident conflicts of interest. It is irrelevant that insurance companies were not directly involved in the trial and insufficient that the investigators disclosed these links in their published research. Given this serious omission, the consent obtained from the 641 trial participants is of questionable legitimacy.

Such flaws are unacceptable in published research; they cannot be defended or explained away. The PACE investigators have repeatedly tried to address these concerns. Yet their efforts to date—in journal correspondence, news articles, blog posts, and most recently in their response to Wilshire et al. in Fatigue[8]—have been incomplete and unconvincing.

The PACE trial compounded these errors by using a case definition for the illness that required only one symptom–six months of disabling, unexplained fatigue. A 2015 report from the U.S. National Institutes of Health recommended abandoning this single-symptom approach for identifying patients.[9] The NIH report concluded that this broad case definition generated heterogeneous samples of people with a variety of fatiguing illnesses, and that using it to study ME/CFS could “impair progress and cause harm.”

PACE included sub-group analyses of two alternate and more specific case definitions, but these case definitions were modified in ways that could have impacted the results. Moreover, an unknown number of prospective participants might have met these alternate criteria but been excluded from the study by the initial screening.

To protect patients from ineffective and possibly harmful treatments, White et al.’s recovery claims cannot stand in the literature. Therefore, we are asking Psychological Medicine to retract the paper immediately. Patients and clinicians deserve and expect accurate and unbiased information on which to base their treatment decisions. We urge you to take action without further delay.

Sincerely,

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

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

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

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

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

Molly Brown, PhD
Assistant Professor
Department of Psychology
DePaul University
Chicago, Illinois, USA

John Chia, MD
Clinician and Researcher
EVMED Research
Lomita, California, USA

Todd E. Davenport, PT, DPT, MPH, OCS
Associate Professor
Department of Physical Therapy
University of the Pacific
Stockton, California, USA

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

Simon Duffy, PhD, FRSA
Director
Centre for Welfare Reform
Sheffield, UK

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

Derek Enlander, MD
New York, New York, USA

Meredyth Evans, PhD
Clinical Psychologist and Researcher
Chicago, Illinois, USA

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

Robert F. Garry, PhD
Professor of Microbiology and Immunology
Tulane University School of Medicine
New Orleans, Louisiana, USA

Keith Geraghty, PhD
Honorary Research Fellow
Division of Population Health, Health Services Research & Primary Care
School of Health Sciences
University of Manchester
Manchester, UK

Ian Gibson, PhD
Former Member of Parliament for Norwich North
Former Dean, School of Biological Sciences
University of East Anglia
Honorary Senior Lecturer and Associate Tutor
Norwich Medical School
University of East Anglia
Norwich, UK

Rebecca Goldin, PhD
Professor of Mathematics
George Mason University
Fairfax, Virginia, USA

Ellen Goudsmit, PhD, FBPsS
Health Psychologist (retired)
Former Visiting Research Fellow
University of East London
London, UK

Maureen Hanson, PhD
Liberty Hyde Bailey Professor
Department of Molecular Biology and Genetics
Cornell University
Ithaca, New York, USA

Malcolm Hooper, PhD
Emeritus Professor of Medicinal Chemistry
University of Sunderland
Sunderland, UK

Leonard A. Jason, PhD
Professor of Psychology
DePaul University
Chicago, Illinois, USA

Michael W. Kahn, MD
Assistant Professor of Psychiatry
Harvard Medical School
Boston, Massachusetts, USA

Jon D. Kaiser, MD
Clinical Faculty
Department of Medicine
University of California, San Francisco
San Francisco, California, USA

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

Betsy Keller, PhD
Department of Exercise and Sports Sciences
Ithaca College
Ithaca, New York, USA

Nancy Klimas, MD
Director, Institute for Neuro-Immune Medicine
Nova Southeastern University
Director, Miami VA Medical Center GWI and CFS/ME Program
Miami, Florida, USA

Andreas M. Kogelnik, MD, PhD
Director and Chief Executive Officer
Open Medicine Institute
Mountain View, California, USA

Eliana M. Lacerda, MD, MSc, PhD
Clinical Assistant Professor
Disability & Eye Health Group/Clinical Research Department
Faculty of Infectious and Tropical Diseases
London School of Hygiene & Tropical Medicine
London, UK

Charles W. Lapp, MD
Medical Director
Hunter-Hopkins Center
Charlotte, North Carolina, USA
Assistant Consulting Professor
Department of Community and Family Medicine
Duke University School of Medicine
Durham, North Carolina, USA

Bruce Levin, PhD
Professor of Biostatistics
Columbia University
New York, New York, USA

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

Vincent C. Lombardi, PhD
Director of Research
Nevada Center for Biomedical Research
Reno, Nevada, USA

Alex Lubet, PhD
Professor of Music
Head, Interdisciplinary Graduate Group in Disability Studies
Affiliate Faculty, Center for Bioethics
Affiliate Faculty, Center for Cognitive Sciences
University of Minnesota
Minneapolis, Minnesota, USA

Steven Lubet
Williams Memorial Professor of Law
Northwestern University Pritzker School of Law
Chicago, Illinois, USA

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

Patrick E. McKnight, PhD
Professor of Psychology
George Mason University
Fairfax, Virginia, USA

Jose G. Montoya, MD, FACP, FIDSA
Professor of Medicine
Division of Infectious Diseases and Geographic Medicine
Stanford University School of Medicine
Stanford, California, USA

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

Henrik Nielsen, MD
Specialist in Internal Medicine and Rheumatology
Copenhagen, Denmark

James M. Oleske, MD, MPH
François-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, USA

Elisa Oltra, PhD
Professor of Molecular and Cellular Biology
Catholic University of Valencia School of Medicine
Valencia, Spain

Richard Podell, MD, MPH
Clinical Professor
Department of Family Medicine
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey, USA

Nicole Porter, PhD
Psychologist in Private Practice
Rolling Ground, Wisconsin, USA

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

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

Anders Rosén, MD
Professor of Inflammation and Tumor Biology
Department of Clinical and Experimental Medicine
Division of Cell Biology
Linköping University
Linköping, Sweden

Peter C. Rowe, MD
Professor of Pediatrics
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA

William Satariano, PhD
Professor of Epidemiology and Community Health
University of California, Berkeley
Berkeley, California, USA

Ola Didrik Saugstad, MD, PhD, FRCPE
Professor of Pediatrics
University of Oslo
Director and Department Head
Department of Pediatric Research
University of Oslo and Oslo University Hospital
Oslo, Norway

Charles Shepherd, MB, BS
Honorary Medical Adviser to the ME Association
Buckingham, UK

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

Donald R. Staines, MBBS, MPH, FAFPHM, FAFOEM
Clinical Professor
Menzies Health Institute Queensland
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, USA

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

Staci Stevens, MA
Founder, Exercise Physiologist
Workwell Foundation
Ripon, California, USA

Julian Stewart, MD, PhD
Professor of Pediatrics, Physiology and Medicine
Associate Chairman for Patient Oriented Research
Director, Center for Hypotension
New York Medical College
Hawthorne, NY, USA

Leonie Sugarman, PhD
Emeritus Associate Professor of Applied Psychology
University of Cumbria
Carlisle, UK

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

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

David Tuller, DrPH
Lecturer in Public Health and Journalism
University of California, Berkeley
Berkeley, California, USA

Rosemary A. Underhill, MB, BS, MRCOG, FRCSE
Physician and Independent Researcher
Palm Coast, Florida, USA

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

Michael VanElzakker, PhD
Research Fellow, Psychiatric Neuroscience Division
Harvard Medical School & Massachusetts General Hospital
Instructor, Tufts University Psychology
Boston, Massachusetts, USA

Mark VanNess, PhD
Professor of Health, Exercise & Sports Sciences
University of the Pacific
Stockton, California, USA
Workwell Foundation
Ripon, California, USA

Mark Vink, MD
Family Physician
Soerabaja Research Center
Amsterdam, Netherlands

Frans Visser, MD
Cardiologist
Stichting Cardiozorg
Hoofddorp, Netherlands

Tony Ward, MA (Hons), PhD, DipClinPsyc
Registered Clinical Psychologist
Professor of Clinical Psychology
School of Psychology
Victoria University of Wellington
Wellington, New Zealand
Adjunct Professor, School of Psychology
University of Birmingham
Birmingham, UK
Adjunct Professor, School of Psychology
University of Kent
Canterbury, UK

William Weir, FRCP
Infectious Disease Consultant
London, UK

John Whiting, MD
Specialist Physician
Private Practice
Brisbane, Australia

Carolyn Wilshire, PhD
Senior Lecturer
School of Psychology
Victoria University of Wellington
Wellington, New Zealand

Michael Zeineh, MD, PhD
Assistant Professor
Department of Radiology
Stanford University
Stanford, California, USA

Marcie Zinn, PhD
Research Consultant in Experimental Electrical Neuroimaging and Statistics
Center for Community Research
DePaul University
Chicago, Illinois, USA
Executive Director
Society for Neuroscience and Psychology in the Performing Arts
Dublin, California, USA

Mark Zinn, MM
Research Consultant in Experimental Electrophysiology
Center for Community Research
DePaul University
Chicago, Illinois, USA

New individuals added 23 March 2017

Norman E. Booth, PhD, FInstP
Emeritus Fellow in Physics
Mansfield College
University of Oxford
Oxford, UK

Joan Crawford, CPsychol, CEng, CSci, MA, MSc
Chartered Counselling Psychologist
Chronic Pain Management Service
St Helens Hospital
St Helens, UK

Lucy Dechene, PhD
Professor of Mathematics (retired)
Fitchburg State University
Fitchburg, Massachusetts, USA

Valerie Eliot Smith
Barrister and Visiting Scholar
Centre for Commercial Law Studies
Queen Mary University of London
London, UK

Margaret C. Fernald, PhD
Clinical and Research Psychologist
University of Maine
Orono, Maine, USA

Simin Ghatineh, MSc, PhD
Biochemist
London, UK

Alan Gurwitt, M.D.
Former Clinical Child Psychiatry Faculty Member
Yale Child Study Center, New Haven, Connecticut
University of Connecticut School of Medicine, Farmington, Connecticut
Harvard Medical School, Boston, Massachusetts
Co-author of primers on Adult and Pediatric ME/CFS
Clinician in Private Practice (retired)
Boston, Massachusetts, USA

Geoffrey Hallmann, LLB, DipLegPrac
Former Laywer, (Disability And Compensation)
Lismore, Australia

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

Marvin S. Medow, Ph.D.
Professor of Pediatrics and Physiology
Chairman, New York Medical College IRB
Associate Director of The Center for Hypotension
New York Medical College
Hawthorne, New York, USA

Sarah Myhill MB BS
Clinician in Private Practice
Knighton, UK

Pamela Phillips, Dip, Dip. MSc MBACP (registered)
Counsellor in Private Practice
London, UK

Gwenda L Schmidt-Snoek, PhD
Researcher
Former Assistant Professor of Psychology
Hope College
Holland, Michigan, USA

Robin Callender Smith, PhD
Professor of Media Law
Centre for Commercial Law Studies
Queen Mary University of London.
Barrister and Information Rights Judge
London, UK

Samuel Tucker, MD
Former Assistant Clinical Professor of Psychiatry
University of California, San Francisco
San Francisco, California, USA

AM Uyttersprot, MD
Neuropsychiatrist
AZ Jan Portaels
Vilvoorde, Belgium

Paul Wadeson, Bsc, MBChB, MRCGP
GP Principal
Ash Trees Surgery
Carnforth, UK

 

ME/CFS Patient Organizations

25% ME Group
UK

Emerge Australia
Australia

European ME Alliance:

Belgium ME/CFS Association
Belgium

ME Foreningen
Denmark

Suomen CFS-Yhdistys
Finland

Fatigatio e.V.
Germany

Het Alternatief
Netherlands

Icelandic ME Association
Iceland

Irish ME Trust
Ireland

Associazione Malati di CFS
Italy

Norges ME-forening
Norway

Liga SFC
Spain

Riksföreningen för ME-patienter
Sweden

Verein ME/CFS Schweiz
Switzerland

Invest in ME Research
UK

Hope 4 ME & Fibro Northern Ireland
UK

Irish ME/CFS Association
Ireland

Massachusetts CFIDS/ME & FM Association
USA

ME Association
UK

ME/cvs Vereniging
Netherlands

National ME/FM Action Network
Canada

New Jersey ME/CFS Association
USA

Pandora Org
USA

Phoenix Rising
International membership representing many countries

Solve ME/CFS Initiative
USA

Tymes Trust (The Young ME Sufferers Trust)
UK

Wisconsin ME and CFS Association
USA

New Organizations added 23 March 2017

Action CND
Canada

Associated New Zealand ME Society
New Zealand

Chester MESH (ME self-help) group
Chester, UK

German Society for ME/CFS (Deutsche Gesellschaft für ME/CFS)
Germany

Lost Voices Stiftung
Germany

M.E. Victoria Association
Canada

ME North East
UK

ME Research UK
UK

ME Self Help Group Nottingham
UK

ME/CFS and Lyme Association of WA, Inc.
Australia

ME/CFS (Australia) Ltd
Australia

ME/CFS Australia (SA), Inc.
Australia

ME/CVS Stichting Nederland
Netherlands

ME/FM Myalgic Encephalomyelitis and Fibromyalgia Society of British Columbia
Canada

MEAction
International membership representing many countries 
 
Millions Missing Canada
Canada
 
National CFIDS Foundation, Inc.
USA
 
North London ME Network
UK
 
OMEGA (Oxfordshire ME Group for Action)
UK
 
Open Medicine Foundation
USA

Quebec ME Association
Canada
 
The York ME Community
UK
 
Welsh Association of ME & CFS Support
UK
Organization added 29 March 2017
Supportgroup ME and Disability
(Steungroep ME en Arbeidsongeschiktheid)
Groningen, Netherlands

[1] White PD, Goldsmith K, Johnson AL, et al. 2013. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 43(10): 2227-2235.

[2] White PD, Goldsmith KA, Johnson AL, et al. 2011. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 377: 823–836

[3] Racaniello V. 2016. An open letter to The Lancet, again. Virology Blog, 10 Feb. Available at: https://www.virology.ws/2016/02/10/open-letter-lancet-again/ (accessed on 2/24/17).

[4] White PD, Sharpe MC, Chalder T, et al. 2007. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 7: 6.

[5] Tuller D. 2015. Trial by error: the troubling case of the PACE chronic fatigue syndrome trial. Virology Blog, 21-23 Oct. Available at: https://www.virology.ws/2015/10/21/trial-by-error-i/ (accessed on 2/24/17)

[6] Wilshire C, Kindlon T, Matthees A, McGrath S. 2016. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior; published online 14 Dec. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1259724 (accessed on 2/24/17)

[7] PACE Participants Newsletter. December 2008. Issue 3. Available at: http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter3.pdf (accessed on 2/24/17).

[8] Sharpe M, Chalder T, Johnson AL, et al. 2017. Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior; published online 15 Feb. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1288629 (accessed on 2/24/17).

[9] Green CR, Cowan P, Elk R. 2015. National Institutes of Health Pathways to Prevention Workshop: Advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Annals of Internal Medicine 162: 860-865.

An open letter to Psychological Medicine about “recovery” and the PACE trial

by

Sir Robin Murray and Dr. Kenneth Kendler
Psychological Medicine
Cambridge University Press
University Printing House
Shaftesbury Road
Cambridge CB2 8BS
UK

Dear Sir Robin Murray and Dr. Kendler:

In 2013, Psychological Medicine published an article called “Recovery from chronic fatigue syndrome after treatments given in the PACE trial.”[1] In the paper, White et al. reported that graded exercise therapy (GET) and cognitive behavioural therapy (CBT) each led to recovery in 22% of patients, compared with only 7% in a comparison group. The two treatments, they concluded, offered patients “the best chance of recovery.”

PACE was the largest clinical trial ever conducted for chronic fatigue syndrome (also known as myalgic encephalomyelitis, or ME/CFS), with the first results published in The Lancet in 2011.[2] It was an open-label study with subjective primary outcomes, a design that requires strict vigilance to prevent the possibility of bias. Yet PACE suffered from major flaws that have raised serious concerns about the validity, reliability and integrity of the findings.[3] Despite these flaws, White et al.’s claims of recovery in Psychological Medicine have greatly impacted treatment, research, and public attitudes towards ME/CFS.

According to the protocol for the PACE trial, participants needed to meet specific benchmarks on four different measures in order to be defined as having achieved “recovery.”[4] But in Psychological Medicine, White et al. significantly relaxed each of the four required outcomes, making “recovery” far easier to achieve. No PACE oversight committees appear to have approved the redefinition of recovery; at least, no such approvals were mentioned. White et al. did not publish the results they would have gotten using the original protocol approach, nor did they include sensitivity analyses, the standard statistical method for assessing the impact of such changes.

Patients, advocates and some scientists quickly pointed out these and other problems. In October of 2015, Virology Blog published an investigation of PACE, by David Tuller of the University of California, Berkeley, that confirmed the trial’s methodological lapses.[5] Since then, more than 12,000 patients and supporters have signed a petition calling for Psychological Medicine to retract the questionable recovery claims. Yet the journal has taken no steps to address the issues.

Last summer, Queen Mary University of London released anonymized PACE trial data under a tribunal order arising from a patient’s freedom-of-information request. In December, an independent research group used that newly released data to calculate the recovery results per the original methodology outlined in the protocol.[6] This reanalysis documented what was already clear: that the claims of recovery could not be taken at face value.

In the reanalysis, which appeared in the journal Fatigue: Biomedicine, Health & Behavior, Wilshire et al. reported that the PACE protocol’s definition of “recovery” yielded recovery rates of 7 % or less for all arms of the trial. Moreover, in contrast to the findings reported in Psychological Medicine, the PACE interventions offered no statistically significant benefits. In conclusion, noted Wilshire et al., “the claim that patients can recover as a result of CBT and GET is not justified by the data, and is highly misleading to clinicians and patients considering these treatments.”

In short, the PACE trial had null results for recovery, according to the protocol definition selected by the authors themselves. Besides the inflated recovery results reported in Psychological Medicine, the study suffered from a host of other problems, including the following:

*In a paradox, the revised recovery thresholds for physical function and fatigue–two of the four recovery measures–were so lax that patients could deteriorate during the trial and yet be counted as “recovered” on these outcomes. In fact, 13 % of participants met one or both of these recovery thresholds at baseline. White et al. did not disclose these salient facts in Psychological Medicine. We know of no other studies in the clinical trial literature in which recovery thresholds for an indicator actually represented worse health status than the entry thresholds for serious disability on the same indicator.

*During the trial, the authors published a newsletter for participants that included glowing testimonials from earlier participants about their positive outcomes in the trial.[7] An article in the same newsletter reported that a national clinical guidelines committee had already recommended CBT and GET as effective; the newsletter article did not mention adaptive pacing therapy, an intervention developed specifically for the PACE trial. The participant testimonials and the newsletter article could have biased the responses of an unknown number of the two hundred or more people still undergoing assessments—about a third of the total sample.

*The PACE protocol included a promise that the investigators would inform prospective participants of “any possible conflicts of interest.” Key PACE investigators have had longstanding relationships with major insurance companies, advising them on how to handle disability claims related to ME/CFS. However, the trial’s consent forms did not mention these self-evident conflicts of interest. It is irrelevant that insurance companies were not directly involved in the trial and insufficient that the investigators disclosed these links in their published research. Given this serious omission, the consent obtained from the 641 trial participants is of questionable legitimacy.

Such flaws are unacceptable in published research; they cannot be defended or explained away. The PACE investigators have repeatedly tried to address these concerns. Yet their efforts to date—in journal correspondence, news articles, blog posts, and most recently in their response to Wilshire et al. in Fatigue[8]—have been incomplete and unconvincing.

The PACE trial compounded these errors by using a case definition for the illness that required only one symptom–six months of disabling, unexplained fatigue. A 2015 report from the U.S. National Institutes of Health recommended abandoning this single-symptom approach for identifying patients.[9] The NIH report concluded that this broad case definition generated heterogeneous samples of people with a variety of fatiguing illnesses, and that using it to study ME/CFS could “impair progress and cause harm.”

PACE included sub-group analyses of two alternate and more specific case definitions, but these case definitions were modified in ways that could have impacted the results. Moreover, an unknown number of prospective participants might have met these alternate criteria but been excluded from the study by the initial screening.

To protect patients from ineffective and possibly harmful treatments, White et al.’s recovery claims cannot stand in the literature. Therefore, we are asking Psychological Medicine to retract the paper immediately. Patients and clinicians deserve and expect accurate and unbiased information on which to base their treatment decisions. We urge you to take action without further delay.

Sincerely,

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

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

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

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

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

Molly Brown, PhD
Assistant Professor
Department of Psychology
DePaul University
Chicago, Illinois, USA

John Chia, MD
Clinician and Researcher
EVMED Research
Lomita, California, USA

Todd E. Davenport, PT, DPT, MPH, OCS
Associate Professor
Department of Physical Therapy
University of the Pacific
Stockton, California, USA

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

Simon Duffy, PhD, FRSA
Director
Centre for Welfare Reform
Sheffield, UK

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

Derek Enlander, MD
New York, New York, USA

Meredyth Evans, PhD
Clinical Psychologist and Researcher
Chicago, Illinois, USA

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

Robert F. Garry, PhD
Professor of Microbiology and Immunology
Tulane University School of Medicine
New Orleans, Louisiana, USA

Keith Geraghty, PhD
Honorary Research Fellow
Division of Population Health, Health Services Research & Primary Care
School of Health Sciences
University of Manchester
Manchester, UK

Ian Gibson, PhD
Former Member of Parliament for Norwich North
Former Dean, School of Biological Sciences
University of East Anglia
Honorary Senior Lecturer and Associate Tutor
Norwich Medical School
University of East Anglia
Norwich, UK

Rebecca Goldin, PhD
Professor of Mathematics
George Mason University
Fairfax, Virginia, USA

Ellen Goudsmit, PhD, FBPsS
Health Psychologist (retired)
Former Visiting Research Fellow
University of East London
London, UK

Maureen Hanson, PhD
Liberty Hyde Bailey Professor
Department of Molecular Biology and Genetics
Cornell University
Ithaca, New York, USA

Malcolm Hooper, PhD
Emeritus Professor of Medicinal Chemistry
University of Sunderland
Sunderland, UK

Leonard A. Jason, PhD
Professor of Psychology
DePaul University
Chicago, Illinois, USA

Michael W. Kahn, MD
Assistant Professor of Psychiatry
Harvard Medical School
Boston, Massachusetts, USA

Jon D. Kaiser, MD
Clinical Faculty
Department of Medicine
University of California, San Francisco
San Francisco, California, USA

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

Betsy Keller, PhD
Department of Exercise and Sports Sciences
Ithaca College
Ithaca, New York, USA

Nancy Klimas, MD
Director, Institute for Neuro-Immune Medicine
Nova Southeastern University
Director, Miami VA Medical Center GWI and CFS/ME Program
Miami, Florida, USA

Andreas M. Kogelnik, MD, PhD
Director and Chief Executive Officer
Open Medicine Institute
Mountain View, California, USA

Eliana M. Lacerda, MD, MSc, PhD
Clinical Assistant Professor
Disability & Eye Health Group/Clinical Research Department
Faculty of Infectious and Tropical Diseases
London School of Hygiene & Tropical Medicine
London, UK

Charles W. Lapp, MD
Medical Director
Hunter-Hopkins Center
Charlotte, North Carolina, USA
Assistant Consulting Professor
Department of Community and Family Medicine
Duke University School of Medicine
Durham, North Carolina, USA

Bruce Levin, PhD
Professor of Biostatistics
Columbia University
New York, New York, USA

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

Vincent C. Lombardi, PhD
Director of Research
Nevada Center for Biomedical Research
Reno, Nevada, USA

Alex Lubet, PhD
Professor of Music
Head, Interdisciplinary Graduate Group in Disability Studies
Affiliate Faculty, Center for Bioethics
Affiliate Faculty, Center for Cognitive Sciences
University of Minnesota
Minneapolis, Minnesota, USA

Steven Lubet
Williams Memorial Professor of Law
Northwestern University Pritzker School of Law
Chicago, Illinois, USA

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

Patrick E. McKnight, PhD
Professor of Psychology
George Mason University
Fairfax, Virginia, USA

Jose G. Montoya, MD, FACP, FIDSA
Professor of Medicine
Division of Infectious Diseases and Geographic Medicine
Stanford University School of Medicine
Stanford, California, USA

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

Henrik Nielsen, MD
Specialist in Internal Medicine and Rheumatology
Copenhagen, Denmark

James M. Oleske, MD, MPH
François-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, USA

Elisa Oltra, PhD
Professor of Molecular and Cellular Biology
Catholic University of Valencia School of Medicine
Valencia, Spain

Richard Podell, MD, MPH
Clinical Professor
Department of Family Medicine
Rutgers Robert Wood Johnson Medical School
New Brunswick, New Jersey, USA

Nicole Porter, PhD
Psychologist in Private Practice
Rolling Ground, Wisconsin, USA

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

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

Anders Rosén, MD
Professor of Inflammation and Tumor Biology
Department of Clinical and Experimental Medicine
Division of Cell Biology
Linköping University
Linköping, Sweden

Peter C. Rowe, MD
Professor of Pediatrics
Johns Hopkins University School of Medicine
Baltimore, Maryland, USA

William Satariano, PhD
Professor of Epidemiology and Community Health
University of California, Berkeley
Berkeley, California, USA

Ola Didrik Saugstad, MD, PhD, FRCPE
Professor of Pediatrics
University of Oslo
Director and Department Head
Department of Pediatric Research
University of Oslo and Oslo University Hospital
Oslo, Norway

Charles Shepherd, MB, BS
Honorary Medical Adviser to the ME Association
Buckingham, UK

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

Donald R. Staines, MBBS, MPH, FAFPHM, FAFOEM
Clinical Professor
Menzies Health Institute Queensland
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, USA

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

Staci Stevens, MA
Founder, Exercise Physiologist
Workwell Foundation
Ripon, California, USA

Julian Stewart, MD, PhD
Professor of Pediatrics, Physiology and Medicine
Associate Chairman for Patient Oriented Research
Director, Center for Hypotension
New York Medical College
Hawthorne, NY, USA

Leonie Sugarman, PhD
Emeritus Associate Professor of Applied Psychology
University of Cumbria
Carlisle, UK

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

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

David Tuller, DrPH
Lecturer in Public Health and Journalism
University of California, Berkeley
Berkeley, California, USA

Rosemary A. Underhill, MB, BS, MRCOG, FRCSE
Physician and Independent Researcher
Palm Coast, Florida, USA

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

Michael VanElzakker, PhD
Research Fellow, Psychiatric Neuroscience Division
Harvard Medical School & Massachusetts General Hospital
Instructor, Tufts University Psychology
Boston, Massachusetts, USA

Mark VanNess, PhD
Professor of Health, Exercise & Sports Sciences
University of the Pacific
Stockton, California, USA
Workwell Foundation
Ripon, California, USA

Mark Vink, MD
Family Physician
Soerabaja Research Center
Amsterdam, Netherlands

Frans Visser, MD
Cardiologist
Stichting Cardiozorg
Hoofddorp, Netherlands

Tony Ward, MA (Hons), PhD, DipClinPsyc
Registered Clinical Psychologist
Professor of Clinical Psychology
School of Psychology
Victoria University of Wellington
Wellington, New Zealand
Adjunct Professor, School of Psychology
University of Birmingham
Birmingham, UK
Adjunct Professor, School of Psychology
University of Kent
Canterbury, UK

William Weir, FRCP
Infectious Disease Consultant
London, UK

John Whiting, MD
Specialist Physician
Private Practice
Brisbane, Australia

Carolyn Wilshire, PhD
Senior Lecturer
School of Psychology
Victoria University of Wellington
Wellington, New Zealand

Michael Zeineh, MD, PhD
Assistant Professor
Department of Radiology
Stanford University
Stanford, California, USA

Marcie Zinn, PhD
Research Consultant in Experimental Electrical Neuroimaging and Statistics
Center for Community Research
DePaul University
Chicago, Illinois, USA
Executive Director
Society for Neuroscience and Psychology in the Performing Arts
Dublin, California, USA

Mark Zinn, MM
Research Consultant in Experimental Electrophysiology
Center for Community Research
DePaul University
Chicago, Illinois, USA

 

ME/CFS Patient Organizations

25% ME Group
UK

Emerge Australia
Australia

European ME Alliance:

Belgium ME/CFS Association
Belgium

ME Foreningen
Denmark

Suomen CFS-Yhdistys
Finland

Fatigatio e.V.
Germany

Het Alternatief
Netherlands

Icelandic ME Association
Iceland

Irish ME Trust
Ireland

Associazione Malati di CFS
Italy

Norges ME-forening
Norway

Liga SFC
Spain

Riksföreningen för ME-patienter
Sweden

Verein ME/CFS Schweiz
Switzerland

Invest in ME Research
UK

Hope 4 ME & Fibro Northern Ireland
UK

Irish ME/CFS Association
Ireland

Massachusetts CFIDS/ME & FM Association
USA

ME Association
UK

ME/cvs Vereniging
Netherlands

National ME/FM Action Network
Canada

New Jersey ME/CFS Association
USA

Pandora Org
USA

Phoenix Rising
International membership representing many countries

Solve ME/CFS Initiative
USA

Tymes Trust (The Young ME Sufferers Trust)
UK

Wisconsin ME and CFS Association
USA

[1] White PD, Goldsmith K, Johnson AL, et al. 2013. Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychological Medicine 43(10): 2227-2235.

[2] White PD, Goldsmith KA, Johnson AL, et al. 2011. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. The Lancet 377: 823–836

[3] Racaniello V. 2016. An open letter to The Lancet, again. Virology Blog, 10 Feb. Available at: https://www.virology.ws/2016/02/10/open-letter-lancet-again/ (accessed on 2/24/17).

[4] White PD, Sharpe MC, Chalder T, et al. 2007. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurology 7: 6.

[5] Tuller D. 2015. Trial by error: the troubling case of the PACE chronic fatigue syndrome trial. Virology Blog, 21-23 Oct. Available at: https://www.virology.ws/2015/10/21/trial-by-error-i/ (accessed on 2/24/17)

[6] Wilshire C, Kindlon T, Matthees A, McGrath S. 2016. Can patients with chronic fatigue syndrome really recover after graded exercise or cognitive behavioural therapy? A critical commentary and preliminary re-analysis of the PACE trial. Fatigue: Biomedicine, Health & Behavior; published online 14 Dec. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1259724 (accessed on 2/24/17)

[7] PACE Participants Newsletter. December 2008. Issue 3. Available at: http://www.wolfson.qmul.ac.uk/images/pdfs/participantsnewsletter3.pdf (accessed on 2/24/17).

[8] Sharpe M, Chalder T, Johnson AL, et al. 2017. Do more people recover from chronic fatigue syndrome with cognitive behaviour therapy or graded exercise therapy than with other treatments? Fatigue: Biomedicine, Health & Behavior; published online 15 Feb. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1288629 (accessed on 2/24/17).

[9] Green CR, Cowan P, Elk R. 2015. National Institutes of Health Pathways to Prevention Workshop: Advancing the research on myalgic encephalomyelitis/chronic fatigue syndrome. Annals of Internal Medicine 162: 860-865.

Once Again, Lancet Stumbles on PACE

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Last February, Virology Blog posted an open letter to The Lancet and its editor, Dr. Richard Horton, describing the indefensible flaws of the PACE trial of treatments for ME/CFS, the disease otherwise known as chronic fatigue syndrome (link to letter). Forty-two well-regarded scientists, academics and clinicians put their names to the letter, which declared flatly that the flaws in PACE “have no place in published research.” The letter called for a completely independent re-analysis of the PACE trial data, since the authors have refused to publish the results they outlined in their original protocol. The letter was also sent directly to Dr. Horton.

The open letter was based on the extensive investigative report written by David Tuller, the academic coordinator of UC Berkeley’s joint program in journalism and public health, which Virology Blog posted last October (link to report). This report outlines such egregious failings as outcome thresholds that overlapped with entry criteria, mid-trial promotion of the therapies under investigation, failure to provide the original results as outlined in the protocol, failure to adhere to a specific promise in the protocol to inform participants about the investigators’ conflicts of interest, and other serious lapses.

Virology Blog first posted the open letter in November, with six signatories (link to letter). At that time, Dr. Horton’s office responded that he would reply after returning from “traveling.” Three months later, we still had not heard back from Dr. Horton–perhaps he was still “traveling”–so we decided to republish it with many more people signed on.

The day the second open letter was posted, Dr Horton e-mailed me and solicited a letter from the group. (He did not explain where he had been “traveling” for the previous three months.) Here’s what he wrote: “Many thanks for your email. In the interests of transparency, I would like to invite you to submit a letter for publication–please keep your letter to around 500 words. We will then invite the authors of the study to reply to your very serious allegations.”

Dr. Horton’s e-mail clearly indicated that the letter would be published, with the PACE authors’ response to the charges raised; there was no equivocation or possibility of misinterpretation. In good faith, we submitted a letter for publication the following month, with 43 signatories this time, through The Lancet’s online editorial system (see the end of this article for a list of those who signed the letter). After several months with no response, we learned only recently by checking the online editorial system that The Lancet had flatly rejected the letter, with no explanation. No one contacted me to explain the decision or why we were asked to spend time creating a letter that The Lancet clearly had no intention of publishing.

I wrote back to Dr. Horton, pointing out that his behavior was highly unprofessional and requesting an explanation for the rejection. I also asked him if he was in the habit of soliciting letters from busy scientists and researchers that his journal had no actual interest in publishing. I further asked if the journal planned to reconsider this rejection, in light of the recent First-Tier Tribunal decision, which demolished the PACE authors’ bogus reasons for refusing to provide data for independent analysis.

Dr. Horton did not himself apologize or even deign to respond. Instead, Audrey Ceschia, the Lancet’s correspondence editor, replied, explaining that the Lancet editorial staff decided, after discussing the matter with the PACE authors, that the letter did not add anything substantially new to the discussion. She assured us that if we submitted another letter focused on the First-Tier Tribunal decision, it would be “seriously” considered. I’m not sure why she or Dr. Horton think that any such assurance from The Lancet is credible at this point.

The reasons given for the rejection are clearly specious. The letter for publication reflected the matters addressed in the open letter that prompted Dr. Horton’s invitation in the first place, and closely adhered to his directive  to outline our “serious allegations”. If outlining these allegations was not considered publication-worthy by The Lancet, it is incomprehensible to us why Dr. Horton solicited the letter in the first place. Perhaps it was just an effort to hold off further criticism for a period of months while we awaited publication of the letter, unaware of the journal’s intention to reject it. It is certainly surprising that The Lancet appears to have given the PACE authors some power to determine what letters appear in the journal itself.

Dr. Tuller’s investigation, based on the groundbreaking analyses conducted by many savvy patients and advocates since The Lancet published the first PACE results in 2011, has effectively demolished the credibility of the findings. So has a follow-up analysis by Dr. Rebecca Goldin, a math professor at George Mason University and director of Stats.org, a think tank co-sponsored by the American Statistical Association. In short, the PACE study is a sham, with meaningless results. In this case, the emperor truly has no clothes. Dr. Horton and his editorial team at The Lancet are stark naked.

Yet the PACE study remains in the literature. Its recommendation of treatments that are potentially harmful to patients–specifically, graded exercise therapy and cognitive behavior therapy, both designed specifically to increase patients’ activity levels–remains highly influential.

Of particular concern, the PACE findings have laid the groundwork for the MAGENTA study, a so-called “PACE for kids” that will be testing graded exercise therapy in children and adolescents. A feasibility study, sponsored by Royal United Hospitals Bath NHS Foundation Trust, is currently recruiting participants. It is, of course, completely unacceptable that any study should justify itself based on the uninterpretable findings of the PACE trial. The MAGENTA trial should be halted until the PACE authors have done what the First-Tier Tribunal ordered them to do–release their raw data and allow others to analyze it according to the outcomes specified in the PACE trial protocol.

Today, because of the urgency of the issue, we are posting on PubMed Commons the letter that The Lancet rejected. That way readers can judge for themselves whether it adds anything to the current debate.

Please note that the opinions in this blog post are mine only, not those of any of the other signers of the Lancet letter, listed below

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

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

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

Leonard A. Jason, PhD
Professor of Psychology
DePaul University
Chicago, Illinois

Bruce Levin, PhD
Professor of Biostatistics
Columbia University
New York, New York

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

******

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 PC
MECFS and Fibromyalgia clinician
Salt Lake City, Utah

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

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

Robert F. Garry, PhD
Professor of Microbiology and Immunology
Tulane University School of Medicine
New Orleans, Louisiana

Rebecca Goldin, PhD
Professor of Mathematics
George Mason University
Fairfax, Virginia

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

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

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

Patrick E. McKnight, PhD
Professor of Psychology
George Mason University
Fairfax, Virginia

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

William Satariano, PhD
Professor of Epidemiology and Community Health
University of California, Berkeley
Berkeley, California

Paul T Seed MSc CStat CSci
Senior Lecturer in Medical Statistics
King’s College London, Division of Women’s Health
St Thomas’ Hospital
London, England, United Kingdom

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

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

Nigel Speight, MA, MC, BChir, FRCP, FRCPCH, DCH
Pediatrician
Durham, England, United Kingdom

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 and Massachusetts General Hospital
Boston, Massachusetts

Mark Vink, MD
Family Physician
Soerabaja Research Center
Amsterdam, The Netherlands

Prof Dr FC Visser
Cardiologist
Stichting CardioZorg
Hoofddorp, The Netherlands

William Weir, FRCP
Infectious Disease Consultant
London, England, United Kingdom

John Whiting, MD
Specialist Physician
Private Practice
Brisbane, Australia

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

TWiV 397: Trial by error

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Journalism professor David Tuller returns to TWiV for a discussion of the PACE trial for ME/CFS: the many flaws in the trial, why its conclusions are useless, and why the data must be released and re-examined.

You can find TWiV #397 at microbe.tv/twiv, or listen below.

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Download TWiV 397 (67 MB .mp3, 93 min)
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Trial by error, Continued: PACE Team’s Work for Insurance Companies Is “Not Related” to PACE. Really?

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By David Tuller, DrPH

David Tuller is academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley.

In my initial story on Virology Blog, I charged the PACE investigators with violating the Declaration of Helsinki, developed in the 1950s by the World Medical Association to protect human research subjects. The declaration mandates that scientists disclose “institutional affiliations” and “any possible conflicts of interest” to prospective trial participants as part of the process of obtaining informed consent.

The investigators promised in their protocol to adhere to this foundational human rights document, among other ethical codes. Despite this promise, they did not tell prospective participants about their financial and consulting links with insurance companies, including those in the disability sector. That ethical breach raises serious concerns about whether the “informed consent” they obtained from all 641 of their trial participants was truly “informed,” and therefore legitimate.

The PACE investigators do not agree that the lack of disclosure is an ethical breach. In their response to my Virology Blog story, they did not even mention the Declaration of Helsinki or explain why they violated it in seeking informed consent. Instead, they defended their actions by noting that they had disclosed their financial and consulting links in the published articles, and had informed participants about who funded the research–responses that did not address the central concern.

“I find their statement that they disclosed to The Lancet but not to potential subjects bemusing,” said Jon Merz, a professor of medical ethics at the University of Pennsylvania. “The issue is coming clean to all who would rely on their objectivity and fairness in conducting their science. Disclosure is the least we require of scientists, as it puts those who should be able to trust them on notice that they may be serving two masters.”

In their Virology Blog response, the PACE team also stated that no insurance companies were involved in the research, that only three of the 19 investigators “have done consultancy work at various times for insurance companies,” and that this work “was not related to the research.” The first statement was true, but direct involvement in a study is of course only one possible form of conflict of interest. The second statement was false. According to the PACE team’s conflict of interest disclosures in The Lancet, the actual number of researchers with insurance industry ties was four—along with the three principal investigators, physiotherapist Jessica Bavington acknowledged such links.

But here, I’ll focus on the third claim–that their consulting work “was not related to the research.” In particular, I’ll examine an online article posted by Swiss Re, a large reinsurance company. The article describes a “web-based discussion group” held with Peter White, the lead PACE investigator, and reveals some of the claims-assessing recommendations arising from that presentation. White included consulting work with Swiss Re in his Lancet disclosure.

The Lancet published the PACE results in February, 2011; the undated Swiss Re article was published sometime within the following year or so. The headline: “Managing claims for chronic fatigue the active way.” (Note that this headline uses “chronic fatigue” rather than “chronic fatigue syndrome,” although chronic fatigue is a symptom common to many illnesses and is quite distinct from the disease known as chronic fatigue syndrome. Understanding the difference between the two would likely be helpful in making decisions about insurance claims.)

The Swiss Re article noted that the illness “can be an emotive subject” and then focused on the implications of the PACE study for assessing insurance claims. It started with a summary account of the findings from the study, reporting that the “active rehabilitation” arms of cognitive behavioral therapy and graded exercise therapy “resulted in greater reduction of patients’ fatigue and larger improvement in physical functioning” than either adaptive pacing therapy or specialist medical care, the baseline condition. (The three intervention arms also received specialist medical care.)

The trial’s “key message,” declared the article, was that “pushing the limits in a therapeutic setting using well described treatment modalities is more effective in alleviating fatigue and dysfunction than staying within the limits imposed by the illness traditionally advocated by ‘pacing.’”

Added the article: “If a CFS patient does not gradually increase their activity, supported by an appropriate therapist, then their recovery will be slower. This seems a simple message but it is an important one as many believe that ‘pacing’ is the most beneficial treatment.”

This understanding of the PACE research—presumably based on information from Peter White’s web-based discussion—was wrong. Pacing is not and has never been a “treatment.” It is also not one of the “four most commonly used therapies,” as the newsletter article declared, since it has never been a “therapy” either. It is a self-help method practiced by many patients seeking the best way to manage their limited energy reserves.

The PACE investigators did not test pacing. Instead, the intervention they dubbed “adaptive pacing therapy” was an operationalized version of “pacing” developed specifically for the study. Many patients objected to the trial’s form of pacing as overly prescriptive, demanding and unlike the version they practiced on their own. Transforming an intuitive, self-directed approach into a “treatment” administered by a “therapist” was not a true test of whether the self-help approach is effective, they argued–with significant justification. Yet the Swiss Re article presented “adaptive pacing therapy” as if it were identical to “pacing.”

The Swiss Re article did not mention that the reported improvements from “active rehabilitation” were based on subjective outcomes and were not supported by the study’s objective data. Nor did it report any of the major flaws of the PACE study or offer any reasons to doubt the integrity of the findings.

The article next asked, “What can insurers and reinsurers do to assist the recovery and return to work of CFS claimants?” It then described the conclusions to be drawn from the discussion with White about the PACE trial—the “key takeaways for claims management.”

First, Swiss Re advised its employees, question the diagnosis, because “misdiagnosis is not uncommon.”

The second point was this: “It is likely that input will be required to change a claimant’s beliefs about his or her condition and the effectiveness of active rehabilitation…Funding for these CFS treatments is not expensive (in the UK, around £2,000) so insurers may well want to consider funding this for the right claimants.”

Translation: Patients who believe they have a medical disease are wrong, and they need to be persuaded that they are wrong and that they can get better with therapy. Insurers can avoid large payouts by covering the minimal costs of these treatments for patients vulnerable to such persuasion, given the right “input.”

Finally, the article warned that private therapists might not provide the kinds of “input” required to convince patients they were wrong. Instead of appropriately “active” approaches like cognitive behavior therapy and graded exercise therapy, these therapists might instead pursue treatments that could reinforce claimants’ misguided beliefs about being seriously ill, the article suggested.

“Check that private practitioners are delivering active rehabilitation therapies, such as those described in this article, as opposed to sick role adaptation,” the Swiss RE article advised. (The PACE investigators, drawing on the concept known as “the sick role” in medical sociology, have long expressed concern that advocacy groups enabled patients’ condition by bolstering their conviction that they suffered from a “medical disease,” as Michael Sharpe, another key PACE investigator, noted in a 2002 UNUMProvident report. This conviction encouraged patients to demand social benefits and health care resources rather than focus on improving through therapy, Sharpe wrote.)

Lastly, the Swiss Re article addressed “a final point specific to claims assessment.” A diagnosis of chronic fatigue syndrome, stated the article, provided an opportunity in some cases to apply a mental health exclusion, depending upon the wording of the policy. In contrast, a diagnosis of myalgic encephalomyelitis did not.

The World Health Organization’s International Classification for Diseases, or ICD, which clinicians and insurance companies use for coding purposes, categorizes myalgic encephalomyelitis as a neurological disorder that is synonymous with the terms “post-viral fatigue syndrome” and “chronic fatigue syndrome.” But the Swiss Re article stated that, according to the ICD, “chronic fatigue syndrome” can also “alternatively be defined as neurasthenia which is in the mental health chapter.”

The PACE investigators have repeatedly advanced this questionable idea. In the ICD’s mental health section, neurasthenia is defined as “a mental disorder characterized by chronic fatigue and concomitant physiologic symptoms,” but there is no mention of “chronic fatigue syndrome” as a discrete entity. The PACE investigators (and Swiss Re newsletter writers) believe that the neurasthenia entry encompasses the illness known as “chronic fatigue syndrome,” not just the common symptom of “chronic fatigue.”

This interpretation, however, appears to be at odds with an ICD rule that illnesses cannot be listed in two separate places—a rule confirmed in an e-mail from a WHO official to an advocate who had questioned the PACE investigators’ argument. “It is not permitted for the same condition to be classified to more than one rubric as this would mean that the individual categories and subcategories were no longer mutually exclusive,” wrote the official to Margaret Weston, the pseudonym for a longtime clinical manager in the U.K. National Health Service.

Presumably, after White disseminated the good news about the PACE results at the web-based discussion, Swiss Re’s claims managers felt better equipped to help ME/CFS claimants. And presumably that help included coverage for cognitive behavior therapy and graded exercise therapy so that claimants could receive the critical “input” they needed in order to recognize and accept that they didn’t have a medical disease after all.

In sum, contrary to the investigators’ argument in their response to Virology Blog, the PACE research and findings appear to be very much “related to” insurance industry consulting work. The claim that these relationships did not represent “possible conflicts of interest” and “institutional affiliations” requiring disclosure under the Declaration of Helsinki cannot be taken seriously.

Update 11/17/15 12:22 PM: I should have mentioned in the story that, in the PACE trial, participants in the cognitive behavior therapy and graded exercise therapy arms were no more likely to have increased their hours of employment than those in the other arms. In other words, there was no evidence for the claims presented in the Swiss Re article, based on Peter White’s presentation, that these treatments were any more effective in getting people back to work.

The PACE investigators published this employment data in a 2012 paper in PLoS One. It is unclear whether Peter White already knew these results at the time of his Swiss Re presentation on the PACE results.

Update 11/18/15 6:54 AM: I also forgot to mention in the story that the three principal PACE investigators did not respond to an e-mail seeking comment about their insurance industry work. Lancet editor Richard Horton also did not respond to an e-mail seeking comment.

An open letter to Dr. Richard Horton and The Lancet

by

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