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.

  • Sasha

    I’ve got tears in my eyes. As a severely ill patient of nearly thirty years I’ve waited a long time for scientists to feel able to come forward and support patients in this way.

    PACE has been a disaster for patients. In the UK, PACE’s philosophy that we’re not really sick and are just scared of exercise has been catastrophic. We can’t tell people that we have ME/CFS without fear of being mocked or despised. It has made the NHS a frightening place for patients.

    Some patients have been abandoned by their families who couldn’t understand why they wouldn’t just “pull themselves together” and exercise their way out of their illness.

    Thank you so much for doing this. Your support means an enormous amount to patients.

    I hope Richard Horton of The Lancet is listening and will put patients first.

    All eyes are on you, Dr Horton.

  • Valentijn

    Excellent! Now to see if we get a coherent response from The Lancet, other than a) “We’ve responded to some criticisms before, so won’t do so now”, or b) “We’ll pretend to respond but actually talk about something else entirely.”

  • Sasha

    The PACE trial has the potential to be one of the great medical scandals of the past few years. The story has everything: patients’ criticisms ignored, null results magically becoming positive, patients vilified for pointing out what scientists couldn’t or wouldn’t see, insurance industry conflicts of interest, the disabled being despised…

    The Lancet quickly needs to get ahead of this and get on the right side of history. This criticism isn’t going to go away: it’s only going to get louder and more widespread.

    Best to act now, do the right thing, and move on with lessons learned.

  • Graham

    Thank you so much for this! I’ve had ME since 1999, but what hurts most is that my son has had it since 1989, and in all that time the reaction of the medical establishment has been condescending and unrelated to the reality of the illness.

  • pinklil

    45 years and counting with this disease. Are we at last seeing the psych edifice crumbling? The one initiated by Beard and McEvedy ironically in the very same year I first became ill: 1970? All I can say is ‘thank you’. That people of your calibre should choose to work on our behalves is changing the terrain. It’s as though the ground has noticeably shifted in the last 3 weeks. A huge thank you must also go to David Tuller and James Coyne who have been instrumental in bringing this appalling state of affairs to the consciousness of a much wider world than our blighted ME Community. Maybe we at last have a genuine reason to hope based on the knowledge the good people, with the appropriate credentials, are fighting our cause rather than resorting to the mind-play of magical thinking?

  • Laura Vitale

    I have been ill with this disease (chronic mono–>CFS–> CFIDS–>ME) since 1977, and this is the first time I have seen anything like this. It’s stunning and amazing to read a letter that lays the truth out so clearly and boldly regarding the pathetic mess of so-called research that is the PACE study…. which is just one in a long line of multi-decade attempts to deny and dismiss ME/CFS into the waste basket of conveniently created psychological illnesses. I thank you all so much for your efforts. And please keep at it until all such nonsense is exposed for the farce that it truly is.

  • fractal

    Thank you, signatories. I have been diagnosed with CFS and also have relatives that probably also have it, albeit in a milder form. If we ever want to make progress, we need to get the junk science out of the way and support the real scientists.

  • mark

    It is both promising and refreshing to see leading scientists push back against the medical community’s faith in the PACE study, and by extension the widespread perception that CFS is a psychiatric disorder coupled with physical deconditioning. Thank you and please keep up your good work on this subject.

  • disqus_Rv8tqVZbOP

    PACE was not on ME. This ME/CFS propaganda has gone far enough.

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  • disqus_Rv8tqVZbOP

    You will always be dismissed as ME/CFS. ME/CFS and CFS/ME are made up terms and technically not recognized illnesses. There is no WHO recognition or ICD codes for ME/CFS or CFS/ME. PACE is the result, not the cause.

  • disqus_Rv8tqVZbOP

    ME is not just a name for CFS. ME predated CFS by several decades. PACE trial was on CFS, not ME, which has been clearly stated. As such, this ME/CFS misinformation has done more harm than PACE (by transferring and misapplying the results to ME).
    PACE was not a good trial, but the hype has been way overblown. Seems to be used mainly to promote the false ME/CFS agenda, thus contributing to the problem, then complaining about the results.

  • fractal

    My impression is that ME/CFS is used to indicate a group of patients with unexplained and heterogenous symptoms. We need biomarkers before we can start sorting out subgroups.

    I think you’re mistaken to believe that separating ME from CFS would remove patients from the sphere of influence of psychiatry. Severity of symptoms has never stopped them from labelling it a psychosomatic disease. The thinking in psychiatry is that medically unexplained symptoms equals psychosomatic disease, regardless of symptoms or severity.

    ME are CFS are both just labels at this point, and doctors don’t care much about labels.

  • Findlow

    A huge thank you to all the signatories of this letter. To know that scientists of your clout and vast breadth of knowledge, are standing up for those of us who have, for so long, been on the very rough end of willful ignorance and misinformation about ME/CFS, means an enormous amount.

  • Scott

    It would appear The Lancet’s legitimacy is on the line.

  • Pamela Spichiger

    Please listen and redo this study. It is so obvious that corners were cut and the original studies are tainted by the companies paying for them. I have suffered for almost 30 years. At first I was able to manage a half way normal life by slowly pacing myself,but as the years crept by my body could not keep up. I have 12 grandchildren who see me in my bed all of the time. It breaks my heart. I want a life,for however many years I have left.

  • disqus_Rv8tqVZbOP

    Actually they are not just labels, but different diagnoses.
    ME is not unexplained fatigue and symptoms.

    ME is a neurological disease, whereas ‘CFS’ defines a heterogeneous patient group suffering from various conditions which involve the symptom of ‘fatigue.’ Thus NOT the same.

  • Richard Smallfield

    The Lancet must withdraw all articles which promote the PACE Study – and explain its reasons for doing so, by itemising the flaws that have been discovered in the trial.

    Richard Smallfield

  • fractal

    It seems more prudent to adopt the position that we are dealing with diseases that have still not been clearly defined.

  • Victor

    Bravo and thanks to David Tuller and all the signatories!
    Let us hope that high standards of integrity will triumph over personal allegiances and restore the good name to the Lancet.

  • disqus_Rv8tqVZbOP

    No, ME has been clearly defined. No need to mix or conflate with a fatigue syndrome.

  • fractal

    I don’t have confidence in attempts to define a disease without understanding what is wrong in the body and without having a biomarker. Any such definition must be considered an artificial construct.

  • Smiffy51

    We do not need another £5 million wasted on yet more psychobabble, run by psychiatrists with a financial interest in such psychobabble. We need an equivalent amount researching the physical causes of M.E., looking carefully at XMRV and vaccines.

  • disqus_Rv8tqVZbOP

    This is absurd, wrong and backwards. Until there are accurate, agreed upon case definitions, we will never know what is wrong or find biomarkers. And if a cause/biomarker is discovered there is really no need for a case definition as the diagnosis will have been established based on these.

  • Severe ME sufferer

    I absolutely agree that ME and CFS are different (ME being a neurological disease about which much is already known, and of which fatigue is only one – and by no means the most serious – of many possible symptoms; and CFS being a heterogeneous group of patients suffering from fatigue of various causes, some serious, all of whom deserve proper diagnosis, care and appropriate treatment).

    However, that is a very different thing to saying that PACE has nothing to do with ME. The PACE investigators themselves have used mixed and inconsistent terminology with conflicting implications about whether or not PACE studied people with ME. Plus PACE has had an overwhelming and hugely negative impact on the UK NHS perception of what ME is and how people with ME should be treated. Also the UK, among others, (incorrectly) refers to ME as CFS, ME/CFS, and CFS/ME; therefore any conclusions drawn about CFS will be automatically considered to apply to ME, whether this is scientifically accurate or not.

    I am extremely grateful for any attempt to discredit the PACE trial, because it is extremely flawed, unethical, and very poor science. This is not the only battle we face, but it’s not insignificant or irrelevant either, not by any means.

  • Ian McIlroy

    As another patient of nearly thirty years I just wanted to add my thanks to you
    all for doing this. The psychiatric model of ME/CFS that UK and other
    Psychiatrists have promoted vigorously and the allied treatments of CBT/GET have
    for too long in the scientific press gone unchallenged, despite biomedical
    research demonstrating that they were long past their sell by date. It is
    heartening, really heartening, to us patients to see that those days are now
    over! We can only hope that the Lancet will now finally do the right thing and
    not continue to bury it’s head in the sand. The psychiatric model and it’s
    treatments have done tremendous damage in so many ways, but most especially to
    the individual patients.

    I can only echo what Sasha has already said,
    that your support in writing this letter to the Lancet means an enormous amount
    to us patients.

    Thank you again!

  • Keith Bradbury

    Almost speechless, I can not think of much to say or at least add to the comments made by fellow sufferers. I too have waited 30 years for such to happen from the Establishment.

  • I have 2 things that are often misdiagnosed as CFS (Ehlers Danlos syndrome and secondary dysautonomia – Postural Orthostatic Tachycardia syndrome). I want to thank these signatories.

  • ahimsa

    I’m just a patient, not an expert, but I don’t believe that either POTS or EDS are exclusionary diagnoses for either ME or CFS. So depending on your other symptoms (e.g., rapid onset after flu-like illness, symptoms that worsen after exertion) these could be overlapping conditions and not necessarily a misdiagnosis.

    I believe that autonomic dysfunction is listed in the 2011 International Consensus Criteria for Myalgic Encephalomyelitis ( http://www.ncbi.nlm.nih.gov/pubmed/21777306 ). And Orthostatic Intolerance is definitely part of the diagnostic criteria suggested by the Feb. 2015 IOM report ( http://iom.edu/mecfs ).

    Patients with Orthostatic Intolerance (POTS, NMH, etc.) might be a subgroup of ME but it’s a big enough group that it has often been included as diagnostic criteria.

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  • Gord Cross

    @discus – go troll elsewhere. The only thing you haven’t done here is say the PACE trial was a good thing. The details and semantics over which you are arguing are lost on the greater community that don’t understand the difference. You’d rather see the headlines in the newspapers that gloss over the study and provides damaging guidance rather than the researchers being taken to account for a flawed and potentially biased study – all because the study was not on ‘ME’. Think ‘big picture’.

  • Gord Cross

    Thanks very much for standing up for the patients, advocates, care takers and millions affected by this disease. Much appreciated.

  • RhymesWithElena

    brilliant! this gave me goosebumps all over. hugely appreciated, thanks a million!

  • Helle Rasmussen

    Thank you so much! Let’s hope, the editor of The Lancet, Richard Horton, will listen to you and to the more than 10,000 people who have signed the petition “Misleading PACE claims should be retracted”: http://my.meaction.net/petitions/pace-trial-needs-review-now?bucket&source=facebook-share-button&time=1446064269

  • disqus_Rv8tqVZbOP

    ME/CFS does far more harm than PACE, yet all of these so called patient groups promote it. We now have fake ME groups calling themselves ME Advocacy or ME Action that are really about CFS or “ME/CFS.” PACE is a symptom, not the cause. ME/CFS is really the cause or origin of the problems and stigma. “ME/CFS” is really patients false illness belief.

  • disqus_Rv8tqVZbOP

    True, and yes, it is the inconsistent and bogus mix of the ME/CFS and CFS/ME terminology that causes the problems, which so called patient groups promote under the guise of advocacy.

    Not that PACE is insignificant, but this has been way overblown.
    We all know PACE was a “bad,” flawed trial. Perhaps it has been more influential in the UK, but it is not true as has been stated that it is so in the US.

    But in the big picture, reality is that using this issue to further promote the bogus ME/CFS agenda is much more damaging to ME patients than PACE.

    Consider:
    Peter White, Royal Society of Medicine
    https://www.youtube.com/watch?v=JWsFvmuJxMA&feature=youtu.be

    Last 5 mins, White begins talking about Ramsay’s ME, and says that Neuro ME and “CFS/ME” (their prefix) i.e. CFS, are not the same.

    He says that ME is an incurable, neurological disease. He also states that since 20% of the Royal Free ME outbreak showed paralysis, they CANNOT be the same. (25% of patients are known to be severe).

    This is from the horses mouth. Get rid of CFS and PACE and the fatigue nonsense will go away. Much better bang for our buck.

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  • Boka

    The term Myalgic Encephalomyelitis has been included by the World Health Organisation (WHO) in their International Classification of Diseases (ICD), since 1969. The current version ICD-10 lists M.E. under G.93.3 – neurological conditions. It cannot be emphasised too strongly that this recognition emerged from meticulous clinical observation and examination.

  • Boka

    In addition, on 12th February 2014 the WHO publicly confirmed that: “Fibromyalgia, ME/CFS are not included as Mental & Behavioural Disorders in ICD-10, there is no proposal to do so for ICD-11” and that this has been accepted by the UK Parliamentary Under-Secretary of State for Health (Jane Ellison MP) who, on 25th February 2014 stated on the record: “The World Health Organisation is currently developing the 11th version of the International Classification of Diseases, which it aims to publish in 2017. No discussions have taken place between the Department and the WHO on the reclassification of ME/CFS, but the WHO has publicly stated that there is no proposal to reclassify ME/CFS in ICD-11”. In other words, it will remain under G.93.3 – ‘neurological conditions’ … the same as Multiple Sclerosis and Epilepsy!

  • disqus_Rv8tqVZbOP

    Do you have a source for this? The fact remains that there is no classification or ICD code for ME/CFS or CFS/ME. And this paraphrasing is not entirely accurate. CFS is not under G93.3. It is not even included the tabular listing (the main body of the work). Tuller got this wrong as well, and it is often misrepresented. CFS is only mentioned in the alphabetical index as another name for ME. So in a way, one could possibly more accurately say that WHO does not really recognize CFS at all. So great, then let’s just not call it that. End of (the bogus) “ME/CFS” story.

  • Boka
  • disqus_Rv8tqVZbOP

    This is the ICD listing. I asked if you have the source for the above quote that was said to be from WHO (12 February 2014). We ask because these “ME/CFS” groups have been known to summarily change or substitute their own terms.

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  • disqus_Rv8tqVZbOP

    It is not semantics. Name calling is not a mature response when discussing issues. If the study was not on ME, it should not apply to ME. Period. The ME/CFS misinformation does that, not PACE.

  • Gord Cross

    Lil fella – you are not contributing here in the least possible way. Regardless of how YOU see things, regardless of how YOUR knowledge stacks up, regardless of how YOU want things to be (oh the absurdity …) – do a little reading around the internet and you’ll see that post after post from newspapers all around the world refer to PACE as ME/CFS and so the general population – the masses – are getting that message. So I ask again, what are you contributing here – nothing. Go away.

  • disqus_Rv8tqVZbOP

    Actually it is not how I see things, it was stated by the authors. The logical thing would be to stop and correct the erroneous ME/CFS message, not have tantrums when the misinformation is pointed out.

  • Gord Cross

    You don’t give up – you should be an advocate. You still don’t get it … if the faulty PACE results (you do recognize that study has significant issues and lacks any credibility right?) are retracted by the Lancet then the applicability of the results to ‘ME/CFS’ is gone. You’re jumping up and down screaming ‘its not about ME’ but really its the perception of the public/government/ill informed doctors that does matter. Not you. If the study is flawed, its flawed. I’m having a hard time placing your motivation here in this discussion. Are you one of those ‘screw the CFS’ people, I have ME and they are faking? Or worse, you believe in the results and think they apply to those fakers but not the diagnosed ME? Give it a rest – the study is flawed and needs to be retracted. Now, for real, go away.

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  • disqus_Rv8tqVZbOP

    No one is saying that the PACE trial is not flawed. The real problem remains that there are people with CFS who have a variety of things which may be helped by CBT and exercise. ME patients are ALWAYS harmed by exercise. Thus they should not be combined, which ME/CFS does, thus does more harm than one study, no matter how flawed.

  • Boka

    This site has lots of threads linking to different places relating to the whole discussion of NICE guidelines and the WHO classification. Please feel free to follow them all up … and get back to me with any valuable insights:
    http://voicesfromtheshadowsfilm.co.uk/2014/where-can-me-patients-turn-for-help/
    But also if you follow the NICE guidance for conditions and diseases, CFS is now listed synonymously with M.E. under ‘neurological conditions’
    http://www.nice.org.uk/guidance/conditions-and-diseases/neurological-conditions
    And if you want to see how this whole palaver unfolded:
    http://www.meassociation.org.uk/2014/10/nice-guideline-over-to-nhs-england-but-swift-action-to-correct-their-classification-of-mecfs-18-october-2014/
    We have a huge debt of gratitude to our charities for winning this fight for us. The alternative would have been a nightmare!