Trial By Error: HRA Report Does Not Vindicate PACE

By David Tuller, DrPH

Last week, I reported that Bristol University had launched an independent investigation of research led by Professor Esther Crawley, at the request of the UK’s Health Research Authority. Today, the HRA released a report on the PACE trial that has portrayed it as a well-conducted study. GET/CBT supporters are framing this report as a vindication.

In contrast, Professor Bruce Levin, a well-known biostatistician at Columbia, used this choice phrase when discussing PACE–“the height of clinical trial amateurism.” Professor Levin gave a talk last summer titled “How NOT to Conduct a Randomized Clinical Trial,” with PACE as the case study. As I have often noted, epidemiology professors at Berkeley have used PACE in their classes as an excellent example of terrible research. I’ve mostly called it “a piece of crap.”

In assessing the HRA’s findings, it is important to remember that the agency’s remit is relatively narrow—it focuses on process. As the report notes: “Our concern as a regulator is whether the study was properly approved by the Research Ethics Committee (REC).”

The report includes this important disclaimer: “It would not be appropriate for the HRA to seek to resolve…debates about the quality of the study. Discussion of the meaning and robustness of results is how science is expected to proceed.

And this: “We also note that some of the criticisms of the PACE trial which have been brought to our attention are outside our regulatory remit and so we are not in a position to comment on them.”

I disagree with many aspects of this report and will discuss my concerns at length at a later point. But any claim that the HRA has given PACE a blanket clean bill of health is going way beyond what the report itself states. Unfortunately, that won’t stop the GET/CBT ideological brigades from pressing that argument.

Significantly, the HRA report focuses on the 2011 Lancet paper and ignores the 2013 “recovery” paper in Psychological Medicine. For that paper, the investigators made the unilateral decision to weaken all four of the “recovery” criteria laid out in their protocol because, as they have explained, they determined that their initial assessment methods were too “stringent” to demonstrate “recovery.” In other words, they were concerned that their reported “recovery” rates would be too low.

It is obvious, of course, that if you weaken measures because they are too “stringent,” you will automatically get results that look better than those you would have otherwise been able to report. The investigators received no apparent oversight committee approvals for this decision–at least, none is mentioned in the 2013 paper. Obviously, had they received such approvals, they would have cited this fact in defense of their dramatic outcome-switching. It is unclear why the HRA chose to omit this paper from its review of the matter.

For now, I am reposting Virology Blog’s open letter to Dr Richard Horton, editor of The Lancet, from last August. That letter called out PACE’s “unacceptable methodological lapses” and was signed by 114 scientists, academics and other experts. It was also signed by ten members of Parliament and many dozens of patients and advocacy organizations.

The criticisms outlined in this open letters have not been rebutted by the HRA report. The PACE study and resulting papers are still fraught with “unacceptable methodological lapses.”

**********

Dear Dr. Horton:

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

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

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

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

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

Since then, much has happened:

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

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

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

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

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

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

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

Thank you for your quick attention to this matter.

Sincerely,

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

Lisa Alioto, JD
Vice President
Minnesota ME/CFS Alliance
Edina, Minnesota, USA

Michael Allen, PhD
Clinical Psychologist (retired)
San Francisco, California, USA

Christopher Armstrong, PhD
Bio21 Molecular Science & Biotechnology Institute
Department of Biochemistry and Molecular Biology
University of Melbourne
Melbourne, Victoria, Australia

James N. Baraniuk, MD
Professor of Medicine
Georgetown University
Washington, DC, USA

Lisa F. Barcellos, 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

Charlotte Blease, PhD
Fulbright and Marie Curie Research Fellow
General Medicine and Primary Care
Beth Israel Deaconess Medical Center
Harvard Medical School
Boston, Massachusetts, USA

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

John Chia, MD
Physician and Researcher
EV Med Research
Lomita, California, USA

Lily Chu, MD, MSHS
Independent Researcher
Burlingame, California, USA

Barbara Comerford, JD
Attorney in Private practice
Specialist in Disability Law
Paramus, New Jersey, USA

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

Janet L Dafoe, PhD
Child Psychologist in Private Practice
Palo Alto, California, USA

Todd E. Davenport, PT, DPT, MPH, OCS
Professor and Program Director
Department of Physical Therapy
Thomas J. Long School of Pharmacy & Health Sciences
University of the Pacific
Stockton, California, USA
Workwell Foundation
Ripon, California, USA

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

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

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

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

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

Derek Enlander, MD
Clinician in private practice
New York, New York, USA

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

W.A. Faas, MD, LL.M
Insurance Physician
Researcher, Vrije Universiteit Amsterdam
Amsterdam, The Netherlands

Margaret C. Fernald, PhD
Clinical Associate
Department of Psychology
University of Maine
Orono, Maine, USA

Mary Ann Fletcher, PhD
Schemel Professor of NeuroImmune Medicine
Nova Southeastern University
Professor Emeritus
University of Miami School of Medicine
Fort Lauderdale, Florida, 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, MPH, PhD
Honorary Research Fellow
Division of Population Health, Health Services Research & Primary Care
School of Health Sciences
University of Manchester
Manchester, England, UK

Simin Ghatineh, MSc, PhD
Biochemist
London, England, 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, England, UK

Claudia Gillberg, PhD
Fellow, Centre for Welfare Reform
Sheffield, England, UK
Senior Research Associate
National Centre for Lifelong Learning
Jonkoping University
Jonkoping, Sweden

Mike Godwin, JD
Attorney and Author
Distinguished Senior Fellow
R Street Institute
Washington, DC, USA

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

Alan Gurwitt, MD
Clinician in Private Practice (retired)
Associate Clinical Professor
Yale Child Study Center (retired)
New Haven, Connecticut, USA
Associate Clinical Professor
University of Connecticut Dept of Psychiatry (retired)
Storrs, Connecticut, USA
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Boston, Massachusetts, USA

Geoffrey Hallmann, LLB, DipLegPrac
Specialist in Disability and Compensation Law (retired)
Lismore, New South Wales, Australia

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

Malcolm Hooper, PhD, BPharm, MRIC, CChem
Emeritus Professor of Medicinal Chemistry
University of Sunderland
Tyne and Wear, England, UK

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

Daniel Kahn, MD
Professor of Radiology
Carver College of Medicine
University of Iowa Health Care
Chief, Nuclear Medicine Section
Iowa City Veteran’s Affairs Medical Center
Iowa City, Iowa, USA

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

Keith Kahn-Harris, PhD
Associate Lecturer in Sociology
Birkbeck, University of London
London, England, UK

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

David L. Kaufman, MD
Center for Complex Diseases
Mountain View, California
Member, The ME/CFS Collaborative Research Center at Stanford
Palo Alto, California, USA

Betsy Keller, PhD, FACSM
Professor of Exercise & Sport 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
Open Medicine Institute
Mountain View, California, USA

Anthony L. Komaroff, MD
Simcox-Clifford-Higby Distinguished Professor of Medicine
Harvard Medical School
Senior Physician
Brigham and Women’s Hospital
Boston, Massachusetts, USA

Richard Kwiatek, MBBS, FRACP
Rheumatologist and Independent Researcher
Northern Adelaide Local Health Network
Adelaide, South Australia, Australia

Eliana M. Lacerda, MD, MSc, PhD
Clinical Assistant Professor
International Centre for Evidence in Disability
Faculty of Infectious and Tropical Diseases
London School of Hygiene & Tropical Medicine
London, England, UK

Charles W. Lapp, MD
Medical Director
Hunter-Hopkins Center
Charlotte, North Carolina, USA

Keith R. Laws, PhD
Professor of Neurocognitive Psychology
School of Psychology
University of Hertfordshire.
Hertfordshire, England, UK

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

Donald Lewis, MBBS, FRACGP, DRACOG
Medical Director
CFS Discovery
Melbourne, Victoria, Australia

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

Rogier Louwen, PhD
Assistant Professor
Department of Medical Microbiology and Infectious Diseases
Erasmus University Medical Center
Rotterdam, The Netherlands

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

Kristin Luker, PhD
Professor of Sociology Emerita
Professor of Law Emerita
Founding Director, Center on Reproductive Rights and Justice
University of California, Berkeley
Berkeley, California, USA

Darren Lynch, MD
Northampton Integrative Medicine
Northampton, Massachusetts, USA

Countess of Mar
House of Lords
Chair, Forward-ME
London, England, UK

David F. Marks, PhD
Editor
Journal of Health Psychology
& Health Psychology Open
London, England, UK

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

Marlon Maus, MD, DrPH, FACS
DrPH Program Director
School of Public Health
University of California, Berkeley
Berkeley, California, USA

Neil R McGregor, BDS, MDSc, PhD
Clinical Associate Professor
Faculty of Medicine, Dentistry and Health Sciences
Bio21 Molecular Science & Biotechnology Institute
University of Melbourne.
Melbourne, Victoria, Australia

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

Marvin S. Medow, PhD
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

Peter G. Medveczky, MD
Professor of Molecular Medicine
Morsani College of Medicine
University of South Florida
Tampa, Florida, 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
Director, Palo Alto Medical Foundation Toxoplasma Serology Laboratory
National Reference Center for the Study and Diagnosis of Toxoplasmosis
Palo Alto, California, USA

Sarah Myhill, MBBS
Clinician in Private Practice
Knighton, Wales, UK

Luis Nacul, MD, PhD
Clinical Associate Professor
International Centre for Evidence in Disability
Faculty of Infectious and Tropical Diseases
London School of Hygiene & Tropical Medicine
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Zaher Nahle, PhD, MPA
Executive Director
Arthritis National Research Foundation
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Heidi Nicholl, PhD
Chief Executive Officer
Emerge Australia
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James M. Oleske, MD, MPH
François-Xavier Bagnoud Professor of Pediatrics
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Director of Division of Pediatrics Allergy, Immunology & Infectious Diseases
Department of Pediatrics
Rutgers New Jersey Medical School
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Elisa Oltra, PhD
Professor of Molecular and Cellular Biology
Catholic University of Valencia School of Medicine
Valencia, Spain

Nigel Paneth, MD, MPH
University Distinguished Professor
Department of Epidemiology & Biostatistics
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College of Human Medicine
Michigan State University
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Rutgers-Robert Wood Johnson Medical School
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Professor of Microbiology and Immunology
Columbia University
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Michael Scott, PhD
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Psychological Therapies Unit
Liverpool, England, UK

Sarah Selke, MB BCh BAO, CCFP
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Environmental Health Clinic
Women’s College Hospital
Toronto, Ontario

Charles Shepherd, MBBS
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Scientific Director
WorkWell Foundation
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Menzies Health Institute Queensland
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University of California, Berkeley
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Psychiatrist in Private Practice
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University of Calgary
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Professor of Pediatrics, Physiology and Medicine
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New York Medical College
Hawthorne, New York, USA

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

John Swartzberg, MD
Clinical Professor Emeritus
School of Public Health
University of California, Berkeley
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Summer M Redstone Professor of Surgery
Harvard Medical School
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Private Practice
Wakefield Rheumatology
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Samuel Tucker, MD
Assistant Clinical Professor of Psychiatry (retired)
University of California, San Francisco
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Center for Global Public Health
School of Public Health
University of California, Berkeley
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Physician, Independent Researcher
Palm Coast, Florida, USA

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AZ Jan Portaels
Vilvoorde, Belgium

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General Practitioner
Auckland, New Zealand

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University of the Pacific
Stockton, California, USA
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Ripon, California, USA

Mark Vink, MD
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Soerabaja Research Center
Amsterdam, The Netherlands

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

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Solve ME/CFS Initiative
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School of Psychology
Victoria University of Wellington
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Cognitive Neuroscience and Data Science
Center for Community Research
DePaul University
Chicago, Illinois, USA
Associate Editor, BMC Journal of Translational Medicine

__________

Members of Parliament

Sir Edward Davey MP
Kingston and Surbiton, England, UK

David Drew MP
Stroud, England, UK

Patricia Gibson MP
North Ayrshire and Arran, Scotland, UK

Mary Glindon MP
North Tyneside, England, UK

Sandy Martin MP
Ipswich, England, UK

Carol Monaghan MP
Glasgow North West, Scotland, UK

Nicky Morgan MP
Loughborough, England, UK

Alex Sobel MP
Leeds North West, England, UK

Graham Stringer MP
Blackley and Broughton, England, UK

Stephen Timms MP
East Ham, England, UK

__________

Patient/Advocacy Organizations

25% ME GROUP
Support for severe ME sufferers
UK

Action CND
Canada

Action for ME
UK

American ME and CFS Society
USA

Associated New Zealand ME Society
New Zealand

Bury and Bolton ME/CFS & Fibromyalgia Support Group
UK

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

Dr Sarah Myhill’s MAIMES [Medical Abuse In ME Sufferers] Campaign
UK

Emerge Australia
Australia

European ME Alliance:

Belgium ME/CFS Association
Belgium

Research ME-CFS.CZ
Czech Republic

ME Foreningen
Denmark

Suomen CFS-Yhdistys
Finland

Fatigatio e.V.
Germany

Het Alternatief
Netherlands

Hope 4 ME & Fibro Northern Ireland
UK

Icelandic ME Association
Iceland

Irish ME Trust
Ireland

Associazione CFS Onlus-Veneto
Italy

Norges ME-forening
Norway

Liga SFC
Spain

Riksföreningen för ME-patienter
Sweden

Verein ME/CFS Schweiz
Switzerland

Invest in ME Research
UK

German Association for ME/CFS
Deutsche Gesellschaft für ME/CFS e.V.
Germany

Global Advocates ME-ICC
Canada

Group ME – The Hague/Dutch Citizens’ Initiative Recognize ME
The Netherlands

Irish ME/CFS Association
Ireland

Leeds ME Network
UK

Lost Voices Stiftung (Fondation)
Hannover/ Germany

Massachusetts CFIDS/ME & FM Association
USA

#MEAction Network:

#MEAction USA

#MEAction UK

#MEAction Scotland

#MEAction Australia

ME Advocates Ireland
Ireland

ME Alliance-UK
UK

ME Association
UK

ME North East
UK

ME Research UK
UK

ME Victoria
Canada

ME/CFS (Australia) Ltd
Australia

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

ME/CFS Australia (SA), Inc.
Australia

ME/CVS Stichting Nederland
Netherlands

ME/CVS Vereniging
Netherlands

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

Millions Missing Canada
Canada

Minnesota ME/CFS Alliance
USA

National CFIDS Foundation, Inc.
USA

National ME/FM Action Network
Canada

New Jersey ME/CFS Association, Inc.
USA

Norfolk & Suffolk ME Patient/Carer Group
UK

North London ME Network
UK

Nottingham ME Support Group
UK

OMEGA (Oxfordshire ME Group for Action)
UK

Open Medicine Foundation
USA

Pandora Org
USA

Phoenix Rising
International membership representing many countries

Research ME-CFS.CZ
Czech Republic

Science For ME
International membership representing many countries

Sheffield ME and Fibromyalgia Group
UK

Simmaron Research Foundation
USA

Solve ME/CFS Initiative
USA

Steungroep ME en Arbeidsongeschiktheid
The Netherlands

Suomen lääketieteellinen ME/CFS-yhdistys ry
Finland

Tymes Trust (The Young ME Sufferers Trust)
UK

Wake-Up Call Beweging vzw (movement)
Belgium

WAMES (Welsh Association of ME & CFS Support)
Wales, UK

Wisconsin ME and CFS Association
USA

York ME Community
UK

___________

[1] White PD 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

[2] Boseley S. 2011. Study finds therapy and exercise best for ME. The Guardian, 18 Feb. Available at: https://www.theguardian.com/society/2011/feb/18/study-exercise-therapy-me-treatment (accessed on April 23, 2018)

[3] Bleijenberg G, Knoop H. 2011. Chronic fatigue syndrome: where to PACE from here? The Lancet, 377: 786-788

[4] Wilshire C et al. 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, 14 Dec. Available at: http://www.tandfonline.com/doi/full/10.1080/21641846.2017.1259724 (accessed on April 23, 2018)

[5] U.S. Institute of Medicine (now National Academy of Medicine). 2015. Beyond myalgic encephalomyelitis/chronic fatigue syndrome: redefining an illness. The National Academies: Washington, DC, USA.

[6] Tuller D. 2015. Trial by error: the troubling case of the PACE chronic fatigue syndrome trial. VirologyBlog, 21-23 Oct. Available at: http://www.virology.ws/2015/10/21/trial-by-error-i/ (accessed onApril 23, 2018)

[7] Racaniello V. 2016. An open letter to The Lancet, again. VirologyBlog, 10 Feb. Available at: http://www.virology.ws/2016/02/10/open-letter-lancet-again/ (accessed on April 23, 2018)

[8] Rehmeyer J. 2016. Bad science misled millions with chronic fatigue syndrome. Here’s how we fought back. STAT, 21 Sept. Available at: https://www.statnews.com/2016/09/21/chronic-fatigue-syndrome-pace-trial/ (accessed on April 23, 2018)

[9] Geraghty K. 2017. ‘PACE-Gate’: when clinical trial evidence meets open data access. Journal of Health Psychology, 22: 1106-1112

[10] Wilshire C et al. 2018. Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT. BMC Psychology; published online 22 March. Available at: https://bmcpsychology.biomedcentral.com/articles/10.1186/s40359-018-0218-3 (accessed on April 23, 2018)

[11] Smith M et al. 2016. Diagnosis and treatment of myalgic encephalomyelitis/chronic fatigue syndrome; addendum. U.S. Agency for Healthcare Research and Quality. July. Available at: https://www.ncbi.nlm.nih.gov/books/NBK379582/ (accessed on April 23, 2018)

[12] Rehmeyer J, Tuller D. 2017. Why did it take the CDC so long to reverse course on debunked treatments for chronic fatigue syndrome? STAT, 25 Sept. Available at: https://www.statnews.com/2017/09/25/chronic-fatigue-syndrome-cdc/ (accessed on April 23, 2018)

[13] Whipple T. 2017. Mutiny by ME sufferers forces a climbdown on exercise treatment. The Times, 25 Sept.

[14] Health Council of the Netherlands. 2018. More scientific research on ME/CFS is needed to serve patients better. 19 March. Available at: https://www.gezondheidsraad.nl/en/news/more-scientific-research-on-mecfs-is-needed-to-serve-patients-better (accessed on April 23, 2018)

[15] Tucker M. 2018. Much can be done to ease ‘chronic fatigue syndrome’ symptoms. Medscape, 12 March. Available at: https://www.medscape.com/viewarticle/893766 (accessed on April 23, 2018)

{ 12 comments… add one }
  • Alex Young aka alex3619 6 February 2019, 9:00 pm

    Quite so. Rather than vindicating PACE, the HRA has established its limitations in assessing “science” like PACE.

  • Clyde 6 February 2019, 9:09 pm

    In what disease can you be disabled and cured at the same time?

    If PACE was well conducted then future well conducted studies can prove patients simultaneously have cancer and are cancer free.
    And patients could both have and not have Parkinsons disease.
    Thats absurd.

    On the plus side that would save on the cost of chemotherapy…
    Until patients who were curable start dying…

  • Couch Turnip 7 February 2019, 2:16 am

    This surely demonstrates –
    a) what an ineffectual body the HRA is. It’s clearly not up to the job of regulating the research environment when so much falls outside its remit. A body that was designed to protect patients now seems to deny patients any voice or recognition. Jonathan Montgomery repeatedly refers to those challenging the PACE trial as ‘critics of the trial’. It seems that he can’t bring himself to describe them as, or as including, ‘patients’ or ‘patient representatives’, but perhaps that would give them a morsel of power/influence that he would rather they didn’t have? Why would anyone agree to participate in UK research when patients are treated so dismissively by the HRA?

    b) that the SMC is a highly biased organization serving a select group and should be shut down. They have proved this by publishing Michael Sharpe’s statement as an example of ‘expert reaction’. It cannot be deduced from the HRA letter that CBT and GET are either safe or helpful treatments as Sharpe implies. The HRA letter makes clear that the debate about the scientific merit (or otherwise) of the PACE Trial study is still ongoing.

    Meanwhile patients continue to suffer in the most horrific ways with little or no meaningful support from the NHS. The British Establishment is acting at its very worst. And they wonder why politics is going the way it is!

  • Peter Trewhitt 7 February 2019, 7:16 am

    Although I understand that the RHA is there to ensure proper research ethics not to police inadequate science, I am very concerned about their failure to address a number of issues:

    1. The failure to fully declare conflicts of interest on the part of researchers means they can not be said to have informed consent.
    2. It is not clear that they had unambiguous ethical aproval for their outcome switching and lowering of recovery thresholds mid study, certainly as others point out it is completely nonsensical that participants could be simultaneously disabled and recovered at baseline, indeed that it was theoretically possible that they could get worse on a measure and count as recovered.
    3. It is bad science to deliberately introduce bias mid study by informing participants that the treatments being examined are regarded as successful, even quoting the Prime Minister’s belief in their efficacy, but is this not also unethical?
    4. There are very real concerns that there was not an adequate system to ensure reporting and recording harms. Anecdotally it has been suggested that at least some participants experienced significant harm but this was not recorded within the study. (Indeed one suspects the researchers’ pre existing commitment to the treatment being evaluated was such they did not believe any harm possible.)

    Further I would argue that the original design of this study was so bad that it could never have told us anything meaningful about ME/CFS. Surely there must be a level at which science becomes so bad that it is unethical to waste vulnerable participants’ already scant resources by asking them to participate.

    To conclude the PACE researchers followed due process in relation to ethical aproval can only be interpreted as indicating either this report has failed to fully address genuine concerns or the current UK ethical aproval system is inadequate (or both).

  • Seven 7 February 2019, 9:35 am

    I think until the law suits are rolling down these organizations, things will not change in UK. Everybody that has been harm need to go to court so we treat it now as criminal case. This is obvious about people that do not care to harm, and is now clear is not ignorance but the damage is been done on purpose, in a way is better happens this way, so you get clear involvement on who the perpetrators are, and when the law comes down on them, they do not have a way to deny their involvement. Let the law suits start rolling!!!

  • jimells 7 February 2019, 9:59 am

    UNUM and other insurers are celebrating that their investments in regulatory capture are paying off handsomely. It would be instructive to follow the careers of top HRA managers to see where they go after their time at HRA is done.

  • Couch Turnip 7 February 2019, 10:54 am

    The health service’s Windrush….. and, like Windrush, they just keep on brushing it under the carpet.

  • Rose Anderson 8 February 2019, 8:41 am

    A lawyer representing the victims of sexual abuse in the Catholic Church commented that the church was “woefully incapable of policing itself”. It’s becoming increasingly clear that the same is true of the British medical establishment.

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