An open letter to The Lancet, again

On November 13th, five colleagues and I released an open letter to The Lancet and editor Richard Horton about the PACE trial, which the journal published in 2011. The study’s reported findings–that cognitive behavior therapy and graded exercise therapy are effective treatments for chronic fatigue syndrome–have had enormous influence on clinical guidelines for the illness. Last October, Virology Blog published David Tuller’s investigative report on the PACE study’s indefensible methodological lapses. Citing these problems, we noted in the letter that “such flaws have no place in published research” and urged Dr. Horton to commission a fully independent review.

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

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


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.


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

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

Leonard A. Jason, PhD
Professor of Psychology
DePaul University

Bruce Levin, PhD
Professor of Biostatistics
Columbia University

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

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


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

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

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

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

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

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

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

John Chia, MD
EV Med Research
Lomita, California

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

William Weir, FRCP
Infectious Disease Consultant
London, England

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

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

Comments on this entry are closed.

  • jane 10 February 2016, 10:12 pm

    Thank you to David and Vincent and all the signers!

  • Victor 10 February 2016, 10:52 pm

    To all the signatories – if only you knew how stirring it is just to read all your names and credentials, knowing what you stand for and what you are committed to achieving. For thousands of people you have never met, that simple alphabetical roll call of names has an aura and a significance you cannot imagine.

  • Mary Schweitzer 10 February 2016, 11:05 pm

    Thank you David. Thank you Vince. Thank you to everyone who signed the letter. We will get to the real science of this disease, I really believe, thanks to your persistence.

  • Luther Blissett 10 February 2016, 11:27 pm

    Thank you all for signing, and Dr. Racaniello for hosting this and related matters.

  • Ches hire 11 February 2016, 3:16 am

    It’s just so nice to see all these vexatious people standing for good science!
    Thanks to all of you!

  • Sally Burch 11 February 2016, 4:58 am

    It is wonderful for ME patients to feel that so many people care so much about what is happening to us because of the PACE trial, and that these same people are determined to follow through on this issue with such determination. Thank you.

  • Sasha 11 February 2016, 6:05 am

    Thank you to everyone who has signed. We patients are so marginalised that without scientists openly joining in the fight, we’ll make no headway. I hope Richard Horton will now reply.

    It means such a lot to us (tears of gratitude are running down my face as I’m writing this).

  • Sasha 11 February 2016, 6:18 am

    BTW, David, you have the wrong link to the original letter. It should be:

  • Ian McIlroy 11 February 2016, 7:40 am

    Thank you again David and Professor Racaniello for your continued support and persistence and thank you to all those who have signed the letter to the Lancet. It means so much to all of us patients.

  • Graham 11 February 2016, 9:16 am

    Back in 2011 I wrote to Richard Horton on behalf of a small group of patients who had similar concerns about the PACE trial. I got no reply, so I wrote to the assistant editor, simply asking for confirmation that they had received my message. I got no reply. The Countess of Mar was supportive, so she wrote to Richard Horton and, guess what, got no reply. Chasing it up with The Lancet’s ombudsman, she didn’t get anywhere either, and when she followed that up was told that the ombudsman was on holiday. I’m guessing he still is, and that Richard Horton has joined him.

    It must be nice there.

  • moon_gazer 11 February 2016, 11:50 am

    I want to sincerely thank all the signatories for their untiring attention to this matter, and not just letting it go by the wayside. I also want to very much thank patient community advocate, Tom Kindlon, who worked hard, and for a long time to try to have this study reassessed. You can read a summary Tom’s contribution here:

  • Findlow 11 February 2016, 1:35 pm

    Yes Tom is a hero, spending so much of his extremely limited energies helping so many others through his research and writing.

  • Findlow 11 February 2016, 1:35 pm

    Thank you so much to all you good clinicians and scientists who have signed this and added the weight of your knowledge and experience to our cause. It means so much; it is such a relief. As a Brit, I hope to see other UK doctors and scientists add their voices and to stand alongside their colleagues Drs Shepherd, Speight and Weir.

  • moon_gazer 11 February 2016, 1:46 pm

    Absolutely agree. We are lucky to have him on ‘our team’! His tenacity has truly paid off.

  • Findlow 11 February 2016, 3:00 pm

    Apologies to Prof. Jonathon Edwards, one of the original signatories and from UK.

  • RhymesWithElena 11 February 2016, 4:28 pm

    Infinite heartfelt thanks! Immensely valuable and hugely appreciated 🙂

  • Sheila Campbell 11 February 2016, 4:39 pm

    Thank you so much Dave, Vince and all the other signatories for pursuing this issue, I love your vexatious behaviour!

  • Vibeke Vind 11 February 2016, 5:21 pm

    Thank you!

  • Paradigm Change 11 February 2016, 6:16 pm

    Thanks to all who signed the letter.

    Lisa Petrison, Ph.D.

  • Gail H-P 11 February 2016, 6:34 pm

    I felt the same way. I teared up thinking “someone believes in us and is standing up for us.” Thank you to everyone who signed.

  • Star Man 11 February 2016, 7:57 pm

    My deepest gratitude to every one who signed this letter.

  • Cort Johnson 12 February 2016, 10:35 am

    Look at all those PhD’s and MD’s! How long can Lancet ignore this?

  • shannah 12 February 2016, 2:46 pm

    Consistent, if nothing else!

  • ahimsa 12 February 2016, 7:59 pm

    Graham, a big thank you for looking into the problems with this research! And a bigger thank you for making wonderful videos to explain the problems. They make things easy enough to understand even for brain-fogged patients.

    For those who have not seen the videos, go to YouTube channel MEAnalysis

  • Luis Henderson 12 February 2016, 8:46 pm

    Thank you so much for your support and persistence in getting to the truth. By the way I don’t think this is ‘vexatious’ at all – a response to a letter from 3 months ago is to be expected out of mere courtesy! Thank you to all who have signed the letter. It really means the world to us patients.

  • Luis Henderson 12 February 2016, 8:50 pm

    Sorry, this is not meant as a reply to Sasha but to the original post!

  • Action CIND 12 February 2016, 11:28 pm

    Thank you to all the individuals that signed.

  • Steve Hawkins 12 February 2016, 11:47 pm

    Good to see such support from so many major names in both somatic and psychological research: But how plain weird that this is necessary to try to get a little data from one paper, in order to see if its conclusions stand up! QMUL seems to have completely forgotten what science is.

  • Elisabeth Royseth 13 February 2016, 3:39 pm

    Thank you!❤️

  • Cathrine engsig 14 February 2016, 9:39 am

    Ignoring this appeal and denying release of data will weaken Richard Hortons credibility and motives. Patients and international bio-medical research have long known and proven that CBT and GET is not a treament for ME/CFS. Thank you to all the intelligent researchers and signatories on this list – this gives new hope.

  • GQ 18 February 2016, 8:31 am

    Thank you Dr Davis

    Thank you Dr Edwards

    Thank you Dr Jason

    Thank you Dr Levin

    Thank you Dr Rancaniello

    Thank you Dr Reingold

    Thank you Dr Ablashi

    Thank you Dr Baranuik

    Thank you Dr Barcellos

    Thank you Dr Bateman

    Thank you Dr Bell

    Thank you Dr Bested

    Thank you Dr Broderick

    Thank you Dr Chia

    Thank you Dr Chu

    Thank you Dr Enlander

    Thank you Dr Fletcher

    Thank you Dr Friedman

    Thank you Dr Kaufman

    Thank you Dr Klimas

    Thank you Dr Lapp

    Thank you Dr Levine

    Thank you Dr Light

    Thank you Dr Marshall-Gradisnik

    Thank you Dr Medveczky

    Thank you Dr Nahle

    Thank you Dr Oleske

    Thank you Dr Podell

    Thank you Dr Shepherd

    Thank you Dr Snell

    Thank you Dr Speight

    Thank you Dr Staines

    Thank you Dr Stark

    Thank you Dr Stein

    Thank you Dr Swartzberg

    Thank you Dr Tompkins

    Thank you Dr Underhill

    Thank you Dr Vallings

    Thank you Dr VanElzakker

    Thank you Dr Weir

    Thank you Dr Zinn

    Thank you Dr Zinn

    And a big Thank you to Dr Tuller!

    On behalf of all the ME community for your courage for standing up for patients who have been abused for far too long by the PACE researchers and for standing up for science. Hopefully more UK Dr’s will now feel safe to sign up in future.

  • MR AIDAN G WALSH 26 March 2016, 6:36 pm

    here we go like YoYo’s back & forth the same happened on XMRV when are all you Great Doctors going to realize that the fatigue is an issue with Ehlers Danlos Syndrome & yes it is Chronic…Drop the

    Stupid Name call it what it really is: EDS types ‘undiagnosed’ Genetic condition same as so called GWI deployed/non deployed…POTS Syncope Autonomic Dysfunction is also a feature

    of Ehlers Danlos Syndrome & no it has nothing to do with Radiation either it has been around since 400 bc & CBT/PACE is a total fraud Lie, has been since day one it is where all the Money for Research goes

    thanks to the small dot on the Map they call the UK thank God I got to see good Doctors who know how to diagnose an illness…The majority have EDS Hypermobility others have Classical type & some have

    rare forms like Vascular VEDS…They are also known in some to even have ‘partial incomplete’ Marfans Syndrome as well & can have what is known as ‘crossover’ multiple types…Supine MRI are useless

    standing/sitting MRI is best…MRA is also used…CFS/ME is a Joke Name Label it’s ‘undiagnosed’ EDS 100% certain…Yes we are Sick & no no no there is no blood test yet for EDS Hypermobile so Stop

    looking you will not find it Belgium Team has found it recently that work needs to be replicated & no the Medicine will not be Pace b.s. or Lyme hysteria LLMD’s

  • Lou Corsius 22 April 2016, 5:13 pm