An open letter to Dr. Richard Horton and The Lancet

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

Comments on this entry are closed.

  • Jo Best 17 November 2015, 12:31 pm

    PACE trial has been influential in US. The principle PACE trial authors have been closely involved in US since CFS was first defined, though it must be noted that their Oxford Criteria for CFS published in 1991 bears little semblance to any of the US CFS criteria. CDC toolkit referencing validity of UK research on CBT and GET for CFS was recently removed. Now UK NICE (national guidelines for doctors) guideline needs to follow suit. The argument that – ME is recognised by WHO and that WHO adding CFS to the alphabetical index of ICD-10 with a ref. to G93.3 does not equate to WHO recognition of CFS as referring to a neurological disorder – is irrelevant in the UK context because in UK, ME was being argued as mass hysteria since before CFS was defined. I absolutely agree that the original compromise in UK of CFS/ME was misguided, but I think that the international consensus (known as Canadian) for ME/CFS was a step in the right direction and that the biomedical research based on that criteria is sound, and I can see and hear from their own mouths that those researchers recognise that the original CFS is ME.

  • Jo Best 17 November 2015, 12:50 pm

    p.s. I mean the original disease (not criteria) that CDC chose to define as CFS, instead if identifying it as WHO ICD-10 G93.3 ME.

  • Jo Best 17 November 2015, 12:58 pm

    Grateful thanks to the esteemed signatories to this letter. The independent UK charity Invest in ME (aka Invest in ME Research) has written a letter and accompanying statement posted here – http://www.investinme.org/IIME-Newslet-1511-01.htm

  • disqus_Rv8tqVZbOP 17 November 2015, 9:39 pm

    Hi Boka, thanks for this. Obviously this is a UK site. So NICE was trying to create or list CFS/ME, but Hooper asks about ME/CFS. This is the absurd mixing and making up terms that credible charities/advocates should take issue with and help to solve.

    That NICE says they are the same is not to say that WHO says they are the same.

    Regarding my question above, this says that Hooper wrote this quote about reclassifying ME/CFS. Since he is clearly one who goes along with ME/CFS, would assume that this was his take and wording. Because there is no way to reclassify that which has never had WHO classification.

    Gratitude to charities? For what? As this page lists as the confusion of the classification, these charities help create and contribute to it.

  • disqus_Rv8tqVZbOP 17 November 2015, 9:55 pm

    I am assuming that you are in the UK? Because I do not see how PACE is influential in the US. It is not cited or referenced in any US material. Nor have PACE authors been involved in the US anywhere that I have seen. And the toolkit referencing PACE was removed a while back.

    Yes there was an argument that speculating that ME was mass hysteria, but was hardly proven as a theory.

    The International Consensus Criteria was for ME. The Canadian criteria is for ME/CFS. Whatever ‘original CFS’ was, it did not and does not define or describe ME or any other neurological illness.

    I apologize as this may be getting way off topic.

  • Boka 18 November 2015, 7:37 pm

    This is so complicated Discus … but this is the best I can do … whilst keeping it succint!
    http://www.name-us.org/defintionspages/DefinitionsArticles/Hoopersdescription.pdf

  • disqus_Rv8tqVZbOP 19 November 2015, 11:08 am

    Yes it is, but we should try to uncomplicate it while not sacrificing accuracy. Again, this is written from the ME/CFS perspective to force this narrative, but is not terribly accurate.

    Always nondescript pronouns, notice ME/CFSers default position is to swap in “this illness” or “our illness.”

    Talking about CFS, then says PVFS is an alternative term. WHO does not say this.

    Relies on the CFS is not chronic fatigue, which in the real world is a pretty lame stance.

    Then states “benign ME (ME/CFS/PVFS) …” I think this is again his take, not the WHO. Promotes his opinion as fact. Just the typical CFS, ME, ME/CFS, CFIDS watevs….

    And bottom line, WHO does not recognize “ME/CFS” as any diagnostic entity.

    ME/CFS is frankly mostly say-so and opinion, which is very harmful to ME patients. It turns the argument on its head and presents the problem as the solution, This is not advocacy.

  • Sparrow 20 November 2015, 10:37 pm

    Thank you for this.

  • GQ 7 December 2015, 4:08 pm

    Thank you very much Drs Davis, Edwards, Jason, Levin, Racaniello and Reingold. You have been very brave to stand up and speak up for some of the most severely disabled people in society. No-one in the UK NHS has been brave enough and able to stand up to these psychiatrists who have caused great harm, injury and abuse to people with ME since they became involved in “treating” or as many feel terrorising people with ME.

  • dfwmom 15 January 2016, 10:55 am

    I am so grateful to the medical experts who stepped forward and did the right thing in this matter. I realize that acts of such overt honesty can invite retribution. They have exposed themselves to professional risk in order to shed light on corruption and dishonesty, so that when patients rely on doctors who are guided by medical research, that research will be honest and reliable. It is time to clean house with regard to the PACE trial. It’s a big giant stinking mess that needs to be thoroughly sanitized.

  • Boka 30 May 2016, 10:51 pm

    Hello my friend! It’s been a while, but I came across this recently and thought you might find it interesting!
    http://www.name-us.org/defintionspages/DefHooper.htm