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.

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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

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Dharam V. Ablashi, DVM, MS, Dip Bact

Scientific Director, HHV-6 Foundation

Former Senior Investigator

National Cancer Institute, NIH

Bethesda, Maryland

James N. Baraniuk, MD

Professor, Department of Medicine,

Georgetown University

Washington, D.C.

Lisa F. Barcellos, PhD, MPH

Professor of Epidemiology

School of Public Health

California Institute for Quantitative Biosciences

University of California

Berkeley, California

Lucinda Bateman, MD

Medical Director, Bateman Horne Center

Salt Lake City, Utah

David S. Bell, MD

Clinical Associate Professor of Pediatrics

State University of New York at Buffalo

Buffalo, New York

Alison C. Bested MD FRCPC

Clinical Associate Professor of Hematology

University of British Columbia

Vancouver, British Columbia, Canada

Gordon Broderick, PhD

Director, Clinical Systems Biology Group

Institute for Neuro Immune Medicine

Professor, Dept of Psychology and Neuroscience

College of Psychology

Nova Southeastern University

Miami, Florida

John Chia, MD

Clinician/Researcher

EV Med Research

Lomita, California

Lily Chu, MD, MSHS

Independent Researcher

San Francisco, California

Derek Enlander, MD, MRCS, LRCP

Attending Physician

Mount Sinai Medical Center, New York

ME CFS Center, Mount Sinai School of Medicine

New York, New York

Mary Ann Fletcher, PhD

Schemel Professor of Neuroimmune Medicine

College of Osteopathic Medicine

Nova Southeastern University

Professor Emeritus, University of Miami School of Medicine

Fort Lauderdale, Florida

Kenneth Friedman, PhD

Associate Professor of Pharmacology and Physiology (retired)

New Jersey Medical School

University of Medicine and Dentistry of NJ

Newark, New Jersey

David L. Kaufman, MD,

Medical Director

Open Medicine Institute

Mountain View, California

Nancy Klimas, MD

Professor and Chair, Department of Clinical Immunology

Director, Institute for Neuro-Immune Medicine

Nova Southeastern University

Director, GWI and ME/CFS Research, Miami VA Medical Center

Miami, Florida

Charles W. Lapp, MD

Director, Hunter-Hopkins Center

Assistant Consulting Professor at Duke University Medical Center

Charlotte, North Carolina

Susan Levine, MD

Clinician, Private Practice

New York, New York

Visiting Fellow, Cornell University

Ithaca, New York

Alan R. Light, PhD

Professor, Department of Anesthesiology and Department of Neurobiology and Anatomy

University of Utah

Salt Lake City, Utah

Sonya Marshall-Gradisnik, PhD

Professor and Co-Director

National Centre for Neuroimmunology and Emerging Diseases

Griffith University

Queensland, Australia

Peter G. Medveczky, MD

Professor, Department of Molecular Medicine, MDC 7

College of Medicine

University of South Florida

Tampa, Florida

Zaher Nahle, PhD, MPA

Vice President for Research and Scientific Programs

Solve ME/CFS Initiative

Los Angeles, California

James M. Oleske, MD, MPH

Francois-Xavier Bagnoud Professor of Pediatrics

Senator of RBHS Research Centers, Bureaus, and Institutes

Director, Division of Pediatrics Allergy, Immunology & Infectious Diseases

Department of Pediatrics

Rutgers – New Jersey Medical School

Newark, New Jersey

Richard N. Podell, M.D., MPH

Clinical Professor

Rutgers Robert Wood Johnson Medical School

New Brunswick, New Jersey

Charles Shepherd, MB, BS

Honorary Medical Adviser to the ME Association

London, United Kingdom

Christopher R. Snell, PhD

Scientific Director

WorkWell Foundation

Ripon, California

Nigel Speight, MA, MB, BChir, FRCP, FRCPCH, DCH

Pediatrician

County Durham, United Kingdom

Donald Staines, MBBS MPH FAFPHM FAFOEM

Professor and Co-Director

National Centre for Neuroimmunology and Emerging Diseases

Griffith University

Queensland, Australia

Philip B. Stark, PhD

Professor of Statistics

University of California, Berkeley

Berkeley, California

Eleanor Stein, MD FRCP(C)

Assistant Clinical Professor

University of Calgary

Calgary, Alberta, Canada

John Swartzberg, MD

Clinical Professor Emeritus

School of Public Health

University of California, Berkeley

Berkeley, California

Ronald G. Tompkins, MD, ScD

Summer M Redstone Professor of Surgery

Harvard University

Boston, Massachusetts

Rosemary Underhill, MB BS.

Physician, Independent Researcher

Palm Coast, Florida

Dr Rosamund Vallings MNZM, MB BS

General Practitioner

Auckland, New Zealand

Michael VanElzakker, PhD

Research Fellow, Psychiatric Neuroscience Division

Harvard Medical School & Massachusetts General Hospital

Boston, Massachusetts

William Weir, FRCP

Infectious Disease Consultant

London, England

Marcie Zinn, PhD

Research Consultant in Experimental Neuropsychology, qEEG/LORETA, Medical/Psychological Statistics

NeuroCognitive Research Institute, Chicago

Center for Community Research

DePaul University

Chicago, Illinois

Mark Zinn, MM

Research consultant in experimental electrophysiology

Center for Community Research

DePaul University

Chicago, Illinois