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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.

Trial By Error, Continued: The New FITNET Trial for Kids

by

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.

The past year has been a disaster for proponents of the PACE trial. They have faced growing international resistance to their exaggerated claims that cognitive behavior therapy and graded exercise therapy are effective treatments for chronic fatigue syndrome, also known as ME/CFS. The recent court-ordered release of key trial data has confirmed what was long self-evident: The PACE authors weakened their outcome criteria mid-stream in ways that allowed them to report dramatically better results for “improvement” (in The Lancet in 2011) and “recovery” (in Psychological Medicine in 2013). In refusing to provide the findings per the original protocol methods, or statistical analyses assessing the impact of the many mid-trial changes, or their actual trial data, they were able to hide their disastrous results for five years.

Yet the PACE authors and their allies continue, astonishingly, to defend the indefensible study, cite its findings approvingly, and push forward with ever more research into behavioral and cognitive interventions. The latest case in point: Esther Crawley, a British pediatrician and a highly controversial figure in the ME/CFS community because of her longtime promotion of the CBT/GET approach. On November 1st, the Science Media Centre in London held a press briefing to tout Dr. Crawley’s current venture–FITNET-NHS, a one-million-pound study of online CBT that is now recruiting and seeks to enroll more than 700 adolescents.

Dr. Crawley is a professor of child health at the University of Bristol. She is also currently recruiting for the MAGENTA study of graded exercise therapy for children with the illness. She is a lead player in the U.K. CFS/ME Research Collaborative, an umbrella organization that is sponsoring an ambitious Big Data effort called MEGA, now in the planning stages. While patients and advocates are desperate for the kind of top-notch biomedical and genetic research being proposed, many oppose MEGA precisely because of the involvement of Dr. Crawley and Peter White, the lead PACE investigator. (Dr. White is reportedly no longer involved in MEGA; Dr. Crawley still definitely is.)

The rationale for FITNET-NHS is that many ME/CFS patients live too far from specialists to obtain adequate care. Therefore, CBT delivered through an online portal, along with e-mail communication with a therapist, could potentially provide a convenient answer for those in such circumstances. The SMC press briefing generated widespread and enthusiastic news coverage. The BBC’s breathless online report about the “landmark” study noted that the online CBT “successfully treats two-thirds of children with chronic fatigue syndrome.” According to the BBC story, the intervention was designed “to change the way the children think of the disease.”

The BBC story and other news reports did not mention that the PACE trial–a foundational piece of evidence for the claim that changing people’s thoughts about the disease is the best way to treat it–has been publicly exposed as nonsense and is the subject of a roiling worldwide scientific debate. The stories also didn’t mention a more recent paper by the authors of the 2012 study from the Netherlands that was the source of the BBC’s claim of a “two-thirds” success rate.

The 2012 study, a Dutch version of FITNET, was published in The Lancet. (Why is The Lancet always involved?) In a subsequent paper published in Pediatrics in 2013, the Dutch team reported no differences among their trial participants at long-term follow-up. In other words, as with the PACE trial itself, any apparent advantages conferred by the investigators’ preferred treatment disappeared after the study was over. (More on the Dutch study below.)

The SMC, a purportedly neutral arbiter of science, actually functions as a cheerleader for research about cognitive and behavioral treatments for ME/CFS. Simon Wessely, a founder of the CBT/GET treatment paradigm and a close colleague of the PACE authors, is on the SMC’s board of trustees. The journalist who wrote the BBC story, James Gallagher, sits on the SMC’s advisory committee, so the reporting wasn’t exactly conducted at arm’s length. This reportorial conflict-of-interest was not disclosed in the BBC story itself.

(In fact, the Countess of Mar, a member of the House of Lords and a longtime advocate for ME/CFS patients, has filed a formal complaint with the BBC to protest its biased reporting on FITNET-NHS. In her complaint, she noted that “the BBC coverage was so hyperbolic and it afforded the FITNET trial so much publicity that it was clearly organised as a counter-punch to the anti-PACE evidence which is now gaining world-wide attention.”)

As a treatment for chronic fatigue syndrome, cognitive behavior therapy is grounded in an unproven hypothesis. According to the theory, the cause of patients’ continuing symptoms is a vicious downward spiral generated by false illness beliefs, a fear of engaging in activity, and progressive deconditioning. Whatever the initial viral or other illness that might have triggered the syndrome, patients are presumed to be currently free of any organic disease. Changing their beliefs through CBT, per the theory, will help encourage them to increase their levels of activity and resume their normal lives.

Here’s the rationale for the treatment from the PACE study itself: “CBT was done on the basis of the fear avoidance theory of chronic fatigue syndrome. This theory regards chronic fatigue syndrome as being reversible and that cognitive responses (fear of engaging in activity) and behavioural responses (avoidance of activity) are linked and interact with physiological processes to perpetuate fatigue. The aim of treatment was to change the behavioural and cognitive factors assumed to be responsible for perpetuation of the participant’s symptoms and disability. Therapeutic strategies guided participants to address unhelpful cognitions, including fears about symptoms or activity by testing them in behavioural experiments.”

The goal of this specific form of CBT, therefore, is to reverse the “reversible” illness by helping patients abandon their “unhelpful” beliefs of having a medical disease. This is definitely not the goal of CBT when it is used to help people cope with cancer, Parkinson’s, or other illnesses; no one claims those diseases are “reversible.” That the PACE authors, Dr. Crawley, and their Dutch colleagues promote CBT as a curative treatment and not simply a management or adaptive strategy is clear from their insistence on using the word “recovery”–a term that has no well-defined or universally understood meaning when it comes to this illness but has a very clear meaning to the general public.

While PACE so far remains in the literature, the study has been rejected by dozens of leading clinicians and academics, in the U.S. and elsewhere. Last February, an open letter to The Lancet signed by 42 experts and posted on Virology Blog condemned its egregious flaws, noting that they “have no place in published research.” The study has even been presented as a case study of bad science in graduate epidemiology seminars and at major scientific gatherings.

*****

Like the work of the PACE authors, Dr. Crawley’s research is fraught with misrepresentations and methodological problems. Like them, she routinely conflates the common symptom of chronic fatigue with the illness called chronic fatigue syndrome–a serious error with potentially harmful consequences. (I will mostly use chronic fatigue syndrome in describing the research because that is the term they use.)

Dr. Crawley favors subjective over objective outcomes. In PACE, of course, the objective measures–like a walking test, a step-test for fitness, and employment status–all failed to demonstrate “recovery” or reflect the reported improvements in the two primary subjective outcomes of physical function and fatigue. FITNET-NHS doesn’t even bother with such measures. The primary outcome is a self-report questionnaire assessing physical function, and almost all the secondary outcomes are also subjective.

This is particularly troubling because FITNET-NHS, like PACE, is non-blinded; that is, both participants and investigators know which intervention they are receiving. Non-blinded studies with subjective outcomes are notoriously vulnerable to bias–even more when the intervention itself involves telling participants that the treatment will make them better, as is the case with the kind of cognitive behavior therapy provided for ME/CFS patients.

The FITNET-NHS study protocol states that participants will be identified using the guidelines developed by NICE–the U.K.’s National Institute for Health and Care Excellence. The protocol describes the NICE guidelines as requiring three months of fatigue, plus one or more of nine additional symptoms: post-exertional malaise, difficulty sleeping, cognitive dysfunction, muscle and/or joint pain, headaches, painful lymph nodes, general malaise, dizziness and/or nausea, or palpitations. In other words, according to the protocol, post-exertional malaise is not required to participate in FITNET-NHS; it is clearly identified as an optional symptom. (In the U.K., the illness can be diagnosed at three months in children, rather than at six months.)

But the proposal’s claim to be following the NICE guidelines does not appear to be true. In the NICE guidelines, post-exertional malaise is not an optional symptom. It is required, as an essential element of the fatigue itself. (In addition, one or more of ten other symptoms must also be present.) To repeat: post-exertional malaise is required in the NICE guidelines, but is not required in the description of the NICE guidelines provided in the FITNET-NHS protocol.

By making this subtle but significant shift–a sleight-of-guideline, so to speak–Dr. Crawley and her colleagues have quietly transformed their prospective cohort from one in which post-exertional malaise is a cardinal characteristic of the illness to one in which it might or might not be present. And they have done this while still claiming–inaccurately–to follow NICE guidelines. As currently described, however, Dr. Crawley’s new study is NOT a study of chronic fatigue syndrome, as she maintains, but of chronic fatigue.

As a result, the actual study participants, like the PACE cohort, will likely be a heterogeneous grab bag of kids suffering from fatigue for any number of reasons, including depression–a common cause of exhaustion and a condition that often responds to psychotherapeutic interventions like CBT. Some or even many participants–an unknown number–will likely be genuine ME/CFS patients. Yet the results will be applied to ALL adolescents identified as having that illness. Since those who actually have it suffer from the required symptom of post-exertional malaise, an intervention that encourages them to increase their activity levels, like CBT, could potentially cause harm.

(I suppose it’s possible the FITNET-NHS protocol’s inaccurate description of the role of post-exertional malaise in the NICE guidelines was inadvertent, a case of sloppiness. If so, it would be an extraordinary oversight, given the number of people involved in the study and the enormous implications of the switch. It is curious that this obvious and jarring discrepancy between the NICE guidelines and the FITNESS-NHS description of them was not flagged during the review process, since it is easy to check whether the protocol language accurately reflects the recommendations.)

Yet Dr. Crawley is experienced at this blurring of categories–she did the same in a study she co-authored in the journal Pediatrics, in January of this year. In the study, “Chronic Fatigue Syndrome at Age 16 Years,” she and colleagues reported that almost one in fifty adolescents suffered from the illness–an extremely high rate that attracted widespread media attention. The main conclusion was described like this: “CFS affected 1.9% of 16-year-olds in a UK birth cohort and was positively associated with higher family adversity.”

However, the Pediatrics study is unreliable as a measure of “chronic fatigue syndrome.” It is of note that this paper, like the FITNET-NHS protocol, also appears to have inaccurately presented the NICE guidelines. According to the Pediatrics paper, NICE calls for a CFS diagnosis after three months of persistent or recurrent fatigue “that is not the result of ongoing exertion, not substantially alleviated by rest, has resulted in a substantial reduction of activities, and has no known cause.” But this description is incomplete–it omits the NICE requirement that the fatigue must include the specific characteristic of post-exertional malaise in order to render a diagnosis of chronic fatigue syndrome.

In the Pediatrics paper, the determination of illness was based not on clinical examination but on parental reports of children’s unexplained fatigue. In a previous study of 13-year-olds that relied on the same U.K. database, Dr. Crawley and her co-authors referred to the endpointappropriately–as “disabling chronic fatigue.” But in this study, they justified changing the endpoint to “chronic fatigue syndrome” by noting that they cross-referenced the parental reports with children’s self-reports of their own fatigue.

Here’s how they explained this shift in nomenclature: ‘In the earlier study, we were unable to confirm a diagnosis of CFS because we had only parental report of fatigue; hence, chronic disabling fatigue was defined as the study outcome. In the present study, parental and child report of fatigue were combined to identify adolescents with CFS.”

This reasoning is incoherent. A child’s confirmation of a parental report of fatigue cannot be taken to indicate the presence of chronic fatigue syndrome–especially without a clinical examination to rule out other possible conditions. Moreover, neither the parental nor child reports appear to have included information about post-exertional malaise, which is required for a diagnosis of chronic fatigue syndrome–even though the Pediatrics study did not mention this requirement in its description of the NICE guidelines. In fact, the authors provided no evidence or data to support their assumption that a double-report of fatigue equaled a case of chronic fatigue syndrome. (How’d that assumption ever pass peer review?)

Moreover, the study itself acknowledged that, when those found to be suffering from high levels of depression were removed, the prevalence of what the investigators called chronic fatigue syndrome was only 0.6 %. And since depression is likely to be highly correlated with chronic fatigue as well as with family adversity, it is not surprising that the study found the apparent association between family adversity and chronic fatigue syndrome that the investigators highlighted in their conclusion. That misinterpretation of their data has likely lent support to the widespread but inaccurate belief that the illness is largely or even partly psychiatric in nature.

In any event, the figure of 0.6 % should have been identified as the prevalence of “chronic disabling fatigue, not attributable to high levels of depression.” Without any further clinical data, to identify either 1.9 % or 0.6 % as the prevalence of chronic fatigue syndrome was unwarranted and irresponsible. Although the authors cited the lack of clinical diagnosis as a limitation, this acknowledgement does not excuse their interpretive leap. To call this a study of chronic fatigue syndrome is really misleading–a serious over-interpretation of the data.

In subsequent correspondence, three professors of pediatrics–Marvin Medow and Julian Stewart from New York Medical College, and Peter Rowe from Johns Hopkins–scolded the study authors for identifying the participants as having chronic fatigue syndrome rather than chronic fatigue. They cited this misclassification as the likely source of the reported link between chronic fatigue syndrome and family adversity. In particular, they challenged diagnoses made without benefit of clinical evaluations.

“An important component of the diagnosis is a physician’s history and physical examination to exclude conditions that could explain the fatigue, including hypothyroidism, heart disease, cancer, liver failure, covert drug abuse, medication side effects, gastrointestinal/nutritional, infectious and psychiatric conditions,” they wrote. The Pediatrics paper, concluded the three pediatricians, “should be titled ‘Chronic Fatigue but not Chronic Fatigue Syndrome at Age 16 Years.'”

In response, the study authors agreed that clinical diagnoses would be more accurate. But they did not address the critical issue of why they decided that two reports of chronic fatigue could be used to identify chronic fatigue syndrome.

*****

The conflation of chronic fatigue and chronic fatigue syndrome is a huge problem in ME/CFS research. That’s why a major report last year from the National Institutes of Health declared that the case definition used in PACE–which required only six months of unexplained fatigue but no other symptoms–could “impair progress and cause harm,” and should be “retired” from use. But Dr. Crawley and her colleagues do not seem to have gotten the message.

At the SMC press briefing presenting FITNET-NHS, one of the experts appearing with Dr. Crawley was Dr. Stephen Holgate, the leader of the CFS/ME Research Collaborative and a professor of immunopharmacology at the University of Southampton. According to the BBC report, he praised the new trial as “high-quality research.” This endorsement suggests that Dr. Holgate, like Dr. Crawley, does not appreciate the significance of the distinction between the symptom of chronic fatigue and the illness called chronic fatigue syndrome–a troubling blind spot. It also suggests that Dr. Holgate is unaware or unconcerned that the main support for the use of CBT in this illness, the PACE trial, has been discredited.

Also at the SMC briefing was Paul McCrone, a professor of health economics from King’s College London and a PACE co-author. Dr. McCrone is serving as the chair of FITNET-NHS’ independent steering committee–another unsettling sign. As I have documented on Virology Blog, Dr. McCrone made false claims as lead author in a 2012 PLoS One paper–and those false claims allowed the PACE authors to declare that CBT and GET were cost-effective. They have routinely cited this fraudulent finding in promoting the therapies.

Beyond the problem of conflating “chronic fatigue” and “chronic fatigue syndrome,” Dr. Crawley’s reliance on the Dutch trial suggests that this previous FITNET study warrants a closer look–especially since the BBC and other news outlets cited its robust claims of success in extolling the U.K. version.

The approach to CBT in the Dutch FITNET trial reflects that in the U.K. Of the online intervention’s 21 modules, according to the protocol for the Dutch study, fourteen “focus on cognitive behavioural strategies and include instructions and exercises on how to identify, challenge and change cognitive processes that contribute to CFS.” Of course, experts outside the CBT/GET/PACE bubble understand that ME/CFS is a physiological disease and that faulty “cognitive processes” have nothing to do with perpetuating or contributing to it.

The Dutch study found that those assigned to FITNET reported less fatigue, greater physical function, and greater school attendance than those in the comparison group, who received standard treatment–referred to as “usual care.” And using a composite definition of “recovery,” the study reported that 63% of those in the FITNET group–just shy of two-thirds–“recovered” at six months, compared to just eight percent in the comparison group. But this apparent success masks a much more complicated reality and cannot be taken at face value, for multiple reasons.

First, the subsequent 2013 paper from the Dutch team found no differences in “recovery” between participants in the two groups at long-term follow-up (on average, 2.7 years after starting). Those in the comparison group improved after the trial and had caught up to the intervention group, so the online CBT conferred no extended advantages or benefits. The researchers argued that the therapy was nonetheless useful because patients achieved gains more quickly. But they failed to consider another reasonable explanation for their results.

Those in usual care were attending in-person sessions at clinics or doctors’ offices. Depending on how often they went, how far they had to travel and how sick they were, the transportation demands could easily have triggered relapses and harmed their health. In contrast, those in the FITNET group could be treated at home. Perhaps they improved not from the treatment itself but from an unintended side effect–the sedentary nature of the intervention allowed them more time to rest. The investigators did not control for this aspect of the online CBT.

Second, the “recovery” figure in the Dutch FITNET study was a post-hoc calculation, as the authors acknowledged. The protocol for the trial included the outcomes to be measured, of course, but the authors did not identify before the trial what thresholds participants would need to meet to be considered “recovered.” The entire definition was constructed only after they saw the results–and the thresholds they selected were extremely lenient. Even two of the PACE authors, in a Lancet commentary praising the Dutch study, referred to the “recovery” criteria as “liberal” and “not stringent.” (In fact, only 36% “recovered” under a more modest definition of “recovery,” but the FITNET authors tucked this finding into an appendix and Dr. Crawley’s FITNET-NHS protocol didn’t mention it.)

Now, the fact that “recovery” was a post-hoc measure doesn’t mean it isn’t valid. But anyone citing this “recovery” rate should do so with caveats and some measure of caution. Dr. Crawley has exhibited no such reticence; in a recent radio interview, she declared flatly that the Dutch participants had made a “full recovery.” (In the same interview, she called PACE “a great, great study.” Then she completely misrepresented the results of the recent reanalyses of the PACE trial data. So, you know, take her words for what they’re worth.)

Given the hyperbole about “recovery,” the public is understandably likely to assume that Dr. Crawley’s new “landmark” study will result in similar success. A corollary of that assumption is that anyone who opposes the study’s approach, like so many in the patient and advocacy communities, could be accused of acting in ways that harm children by depriving them of needed treatment. This would be an unfair charge, since the online CBT being offered is based on the questionable premise that the children harbor untrue cognitions about their illness.

Third, the standard treatments received by the usual care group were described like this: “individual/group based rehabilitation programs, psychological support including CBT face-to-face, graded exercise therapy by a physiotherapist, etc.” In other words, pretty much the kinds of “evidence-based” strategies these Dutch experts and their U.K. colleagues had promoted for years as being effective for chronic fatigue syndrome. In the end, two-thirds of those in usual care received in-person CBT, and half received graded exercise therapy. (Many participants in this arm received more than one form of usual care.)

And yet less than one in ten of the usual care participants were found to have “recovered” at six months, according to the 2012 study. So what does that say about the effectiveness of these kinds of rehabilitative approaches in the first place? In light of the superlative findings for online CBT, why haven’t all chronic fatigue syndrome patients in the Netherlands now been removed from in-person treatments and offered this more convenient option? (Dr. Crawley’s FITNET-NHS proposal tried to explain away this embarrassing finding of the Dutch study by suggesting that those providing usual care were not trained to work with this kind of population.)

Finally, the Dutch study did not report any objective measures of physical performance. Although the study included assessments using an actometer–an ankle bracelet that monitors distance moved–the Lancet paper did not mention those results. In previous studies of cognitive and behavioral treatments for ME/CFS, reported improvements on subjective measures for fatigue or physical function were not accompanied by increases in physical movement, as measured by actometer. And in PACE, of course, the investigators dismissed their own objective measures as irrelevant or non-objective–but only after these outcomes failed to provide the desired results.

In response to correspondence calling for publication of the actometer data, the Dutch investigators refused, noting that “the goal of our treatment was reduction of fatigue and increase in school attendance, not increase in physical activity per se.” This is an inadequate explanation for the decision to withhold data that would shed light on whether participants actually improved in their physical performance as well as in their subjective impressions of their condition. If the actometer data demonstrated remarkable increases in activity levels in the online CBT group, is there any doubt they would have reported it?

In short, the Dutch FITNET study leaves a lot of questions unanswered. So does its U.K. version, the proposed FITNET-NHS. And Dr. Crawley’s recent media blitz–which included a “can’t-we-all-get-along” essay in The New Scientist–did little to quell any of the reasonable qualms observers might have about this latest effort to bolster the sagging fortunes of the CBT/GET/PACE paradigm.

“Patients are desperate for this trial, yet some people are still trying to stop us,” wrote Dr. Crawley in The New Scientist. “The fighting needs to end.”

However, those mysterious and sinister-sounding “some people” cited by Dr. Crawley have very thoughtful and legitimate reasons for questioning the quality of her research. The fighting, as she calls it, is likely to end when Dr. Crawley and her colleagues stop conflating chronic fatigue and chronic fatigue syndrome through the use of loose diagnostic criteria. And when they acknowledge what scientists in the U.S. and around the world now understand: The claim that cognitive and behavioral approaches are effective treatments that lead to “recovery” is based on deeply flawed research.

A Short Postscript:

Several Dutch colleagues have joined Dr. Crawley as part of the FITNET-NHS study. Two of them, Dr. Gijs Bleijenberg from the Radboud University Medical Centre in Nijmegen, and Dr. Hans Knoop from the University of Amsterdam, are among the leaders of the CBT/GET movement in the Netherlands and have collaborated with their U.K. counterparts. Not surprisingly, their work is similarly dodgy.

In a post last year, I dissected a 2011 commentary in The Lancet on the PACE trial, co-authored by Dr. Bleijenberg and Dr. Knoop, in which they argued that 30 percent of the participants in the CBT and GET groups had met “a strict criterion for recovery.” This statement was absurd, since these “strict” thresholds for “recovery” were in fact so lax that participants could get worse during the study and still meet them. Although the problematic nature of the thresholds has been pointed out to Dr. Bleijenberg and Dr. Knoop, they have stood by their nonsensical claim.

Earlier this year, the Dutch parliament asked the Health Council–an independent scientific advisory body–to review the state of evidence related to the illness, including the evidence on treatments like CBT and GET. The Health Council appointed a committee to conduct the review. Among the committee members are Dr. Knoop and colleagues who share his perspective. It remains unclear whether the committee is taking sufficient account of the methodological flaws underpinning the evidence for the CBT/GET paradigm and of the ongoing condemnations of the PACE trial from well-respected scientists. I plan to blog about this situation soon.

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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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

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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