by David Tuller, DrPH

David Tuller is academic coordinator of the concurrent masters degree program in public health and journalism at the University of California, Berkeley.

‘The PACE trial is a fraud.’ Ever since Virology Blog posted my 14,000-essord investigation of the PACE trial last October, I’ve wanted to write that sentence. (I should point out that Dr. Racaniello has already called the PACE trial a “sham,” and I’ve already referred to it as “doggie-poo.” I’m not sure that “fraud” is any worse. Whatever word you use, the trial stinks.)

Let me be clear: I don’t mean “fraud” in the legal sense—I’m not a lawyer–but in the sense that it’s a deceptive and morally bankrupt piece of research. The investigators made dramatic changes from the methodology they outlined in their protocol, which allowed them to report purported “results” that were much, much better than those they would have been able to claim under their originally planned methods. Then they reported only the better-looking “results,” with no sensitivity analyses to analyze the impact of the changes—the standard statistical approach in such circumstances.

This is simply not allowed in science. It means the reported benefits for cognitive behavior therapy and graded exercise therapy were largely illusory–an artifact of the huge shifts in outcome assessments the authors introduced mid-trial. (That’s putting aside all the other flaws, like juicing up responses with a mid-trial newsletter promoting the interventions under investigation, failing to obtain legitimate informed consent from the participants, etc.)

That PACE suffered from serious methodological deficiencies should have been obvious to anyone who read the studies. That includes the reviewers for The Lancet, which published the PACE results for “improvement” in 2011 after what editor Richard Horton has called “endless rounds of peer-review,” and the journal Psychological Medicine, which published results for “recovery” in 2013. Certainly the deficiencies should have been obvious to anyone who read the trenchant letters and commentaries that patients routinely published in response to the egregious errors committed by the PACE team. Even so, the entire U.K. medical, academic and public health establishments refused to acknowledge what was right before their eyes, finding it easier instead to brand patients as unstable, anti-science, and possibly dangerous.

Thanks to the efforts of the incredible Alem Matthees, a patient in Perth, Australia, the U.K.’s First-Tier Tribunal last month ordered the liberation of the PACE trial data he’d requested under a freedom-of-information request. (The brief he wrote for the April hearing, outlining the case against PACE in great detail, was a masterpiece.) Instead of appealing, Queen Mary University of London, the home institution of lead PACE investigator Peter White, made the right decision. On Friday, September 9, the university announced its intention to comply with the tribunal ruling, and sent the data file to Mr. Matthees. The university has a short window of time before it has to release the data publicly.

I’m guessing that QMUL forced the PACE team’s hand by refusing to allow an appeal of the tribunal decision. I doubt that Dr. White and his colleagues would ever have given up their data willingly, especially now that I’ve seen the actual results. Perhaps administrators had finally tired of the PACE shenanigans, recognized that the study was not worth defending, and understood that continuing to fight would further harm QMUL’s reputation. It must be clear to the university now that its own reputational interests diverge sharply from those of Dr. White and the PACE team. I predict that the split will become more apparent as the trial’s reputation and credibility crumble; I don’t expect QMUL spokespeople to be out there vigorously defending the unacceptable conduct of the PACE investigators.

Last weekend, several smart, savvy patients helped Mr. Matthees analyze the newly available data, in collaboration with two well-known academic statisticians, Bruce Levin from Columbia and Philip Stark from Berkeley.  Yesterday, Virology Blog published the group’s findings of the single-digit, non-statistically significant “recovery” rates the trial would have been able to report had the investigators adhered to the methods they outlined in the protocol. That’s a remarkable drop from the original Psychological Medicine paper, which claimed that 22 percent of those in the favored intervention groups achieved “recovery,” compared to seven percent for the non-therapy group.

Now it’s clear: The PACE authors themselves are the anti-science faction. They tortured their data and ended up producing sexier results. Then they claimed they couldn’t share their data because of alleged worries about patient confidentiality and sociopathic anti-PACE vigilantes. The court dismissed these arguments as baseless, in scathing terms. (It should be noted that their ethical concerns for patients did not extend to complying with a critical promise they made in their protocol—to tell prospective participants about “any possible conflicts of interest” in obtaining informed consent. Given this omission, they have no legitimate informed consent for any of their 641 participants and therefore should not be allowed to publish any of their data at all.)

The day before QMUL released the imprisoned data to Mr. Matthees, the PACE authors themselves posted a pre-emptive re-analysis of results for the two primary outcomes of physical function and fatigue, according to the protocol methods. In the Lancet paper, they had revised and weakened their own definition of what constituted “improvement.” With this revised definition, they could report in The Lancetthat approximately 60 % in the cognitive behavior and graded exercise therapy arms “improved” to a clinically significant degree on both fatigue and physical function.

The re-analysis the PACE authors posted last week sought to put the best possible face on the very poor data they were required to release. Yet patients examining the new numbers quickly noted that, under the more stringent definition of “improvement” outlined in the protocol, only about 20 percent in the two groups could be called “overall improvers.”. Solely by introducing a more relaxed definition of “improvement,” the PACE team—enabled by The Lancet’s negligence and an apparently inadequate “endless” review process–was able to triple the trial’s reported success rate..

So now it’s time to ask what happens to the papers already published. The editors have made their feelings clear. I have written multiple e-mails to Lancet editor Richard Horton since I first contacted him about my PACE investigation, almost a year before it ran. He never responded until September 9, the day QMUL liberated the PACE data. Given that the PACE authors’ own analysis showed that the new data showed significantly less impressive results than those published in The Lancet, I sent Dr. Horton a short e-mail asking when we could expect some sort of addendum or correction to the 2011 paper. He responded curtly: “Mr. Tuller–We have no such plans.”

The editors of Psychological Medicine are Kenneth Kendler of Virginia Commonwealth University and Robin Murray of Kings College London. After I wrote to the journal last December, pointing out the problems, I received the following from Dr. Murray, whose home base is KCL’s Department of Psychosis Studies: “Obviously the best way of addressing the truth or otherwise of the findings is to attempt to replicate them. I would therefore like to encourage you to initiate an attempted replication of the study. This would be the best way for you to contribute to the debate…Should you do this, then Psychological Medicine will be most interested in the findings either positive or negative.”

This was not an appropriate response. I told Dr. Murray it was “disgraceful,” given that the paper was so obviously flawed. This week, I wrote again to Dr. Murray and Dr. Kendler, asking if they now planned to deal with the paper’s problems, given the re-analysis by Matthees et al. In response, Dr. Murray suggested that I submit a re-analysis, based on the released data, and Psychological Medicine would be happy to consider it. “We would, of course, send it out to referees for scientific scrutiny in the same manner as we did for the original paper,” he wrote.

I explained that it was his and the journal’s responsibility to address the problems, whether or not anyone submitted a re-analysis. I also noted that I could not improve on the Matthees re-analysis, which completed rebutted the results reported in Psychological Medicine’s paper. I urged Dr. Murray to contact either Dr. Racaniello or Mr. Matthees to discuss republishing it, if he truly wished to contribute to the debate. Finally, I noted that the peer-reviewers for the original paper had okayed a study in which participants could be disabled and recovered simultaneously, so I wasn’t sure if the journal’s assessment process could be trusted.

(By the way, Kings College London, where Dr. Murray is based, is also the home institution of PACE investigator Trudie Chalder as well as Simon Wessely, a close colleague of the PACE authors and president of the Royal College of Psychiatrists*. That could explain Dr. Murray’s inability or reluctance to acknowledge that the “recovery” paper his journal peer-reviewed and published is meaningless.)

Earlier today, the PACE authors posted a blog on The BMJ site, their latest effort to salvage their damaged reputations. They make no mention of their massive research errors and focus only on their supposed fears that releasing even anonymous data will frighten away future research participants. They have provided no evidence to back up this unfounded claim, and the tribunal flatly rejected it. They also state that only researchers who present  “pre-specified” analysis plans should be able to obtain trial data. This is laughable, since Dr. White and his colleagues abandoned their own pre-specified analyses in favor of analyses they decided they preferred much later on, long after the trial started.

They have continued to refer to their reported analyses, deceptively, as “pre-specified,” even though these methods were revised mid-trial. The following point has been stated many times before, but bears repeating: In an open label trial like PACE, researchers are likely to know very well what the outcome trends are before they review any actual data. So the PACE team’s claim that the changes they made were “pre-specified” because they were made before reviewing outcome data is specious. I have tried to ask them about this issue multiple times, and have never received an answer.

Dr. White, his colleagues, and their defenders don’t yet seem to grasp that the intellectual construct they invented and came to believe in—the PACE paradigm or the PACE enterprise or the PACE cult, have your pick—is in a state of collapse. They are used to saying whatever they want about patients—Internet Abuse! Knife-wielding! Death threats!!–and having it be believed. In responding to legitimate concerns and questions, they have covered up their abuse of the scientific process by providing non-answers, evasions and misrepresentations—the academic publishing equivalent of “the dog ate my homework.” Amazingly, journal editors, health officials, reporters and others have accepted these non-responsive responses as reasonable and sufficient. I do not.

Now their work is finally being scrutinized the way it should have been by peer reviewers before this damaging research was ever published in the first place. The fallout is not going to be pretty. If nothing else, they have provided a great gift to academia with their $8 million** disaster—for years to come, graduate students in the U.S., the U.K. and elsewhere will be dissecting PACE as a classic case study of bad research and mass delusion.

*Correction: The original version of the post mistakenly called the organization the Royal Society of Psychiatrists.

**Correction: The original version of the post stated that PACE cost $8 million, not $6.4 million. In fact, PACE cost five million pounds, so the cost in dollars depends on the exchange rate used. The $8 million figure is based on the exchange rate from last October, when Virology Blog published my PACE investigation. But the pound has fallen since the Brexit vote in June, so the cost in dollars at the current exchange rate is lower.

Last October, Virology Blog posted David Tuller’s 14,000-word investigation of the many flaws of the PACE trial (link to article), which had reported that cognitive behavior therapy and graded exercise therapy could lead to “improvement” and “recovery” from ME/CFS. The first results, on “improvement,” were published in The Lancet in 2011; a follow-up study, on “recovery,” was published in the journal Psychological Medicine in 2013.

The investigation by Dr. Tuller, a lecturer in public health and journalism at UC Berkeley, built on the impressive analyses already done by ME/CFS patients; his work helped demolish the credibility of the PACE trial as a piece of scientific research. In February, Virology Blog posted an open letter (link) to The Lancet and its editor, Richard Horton, stating that the trial’s flaws “have no place in published research.” Surprisingly, the PACE authors, The Lancet, and others in the U.K. medical and academic establishment have continued their vigorous defense of the study, despite its glaring methodological and ethical deficiencies.

Today, I’m delighted to publish an important new analysis of PACE trial data—an analysis that the authors never wanted you to see.  The results should put to rest once and for all any question about whether the PACE trial’s enormous mid-trial changes in assessment methods allowed the investigators to report better results than they otherwise would have had. While the answer was obvious from Dr. Tuller’s reporting, the new analysis makes the argument incontrovertible.

ME/CFS patients developed and wrote this groundbreaking analysis, advised by two academic co-authors. It was compiled from data obtained through a freedom-of-information request, pursued with heroic persistence by an Australian patient, Alem Matthees. Since the authors dramatically weakened all of their “recovery” criteria long after the trial started, with no committee approval for the redefinition of “recovery,” it was entirely predictable that the protocol-specified results would be worse. Now we know just how much worse they are.

According to the new analysis, “recovery” rates for the graded exercise and cognitive behavior therapy arms were in the mid-single-digits and were not statistically significant. In contrast, the PACE authors managed to report statistically significant “recovery” rates of 22 percent for their favored interventions. Given the results based on the pre-selected protocol metrics for which they received study approval and funding, it is now up to the PACE authors to explain why anyone should accept their published outcomes as accurate, reliable or legitimate.

The complete text of the analysis is below. A pdf is also available (link to pdf).

***

In the first of two shows recorded at the University of North Carolina in Chapel Hill, Vincent meets up with faculty members to talk about how they got into science, their research on DNA viruses, and what they would be doing if they were not scientists.

You can find TWiV #407 part one at microbe.tv/twiv. Or watch the video above, or listen below.

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Prions are not viruses – they are infectious proteins that lack nucleic acids. Nevertheless, virologists have always been fascinated by prions – they appear in virology textbooks (where else would you put them?) and are taught in virology classes. I’ve written about prions on this blog (five articles, to be exact – look under P in the Table of Contents) and I’m fascinated by their biology and transmission. That’s why the newly solved structure of an infectious prion protein is the topic of the sixth prion article at virology blog.

Spongiform encephalopathies are neurodegenerative diseases caused by misfolding of normal cellular prion proteins. Human spongiform encephalopathies are placed into three groups: infectious, familial or genetic, and sporadic, distinguished by how the disease is acquired initially. In all cases, the pathogenic protein is the host-encoded PrP^C protein with an altered conformation, called PrP^sc. In the simplest case, PrP^Sc converts normal PrP^C protein into more copies of the pathogenic form (illustrated).

The structure of the normal PrP^C protein, solved some time ago, revealed that it is largely alpha-helical with little beta-strand content. The structure of PrP^Sc protein has been elusive, because it forms aggregates and amyloid fibrils. It has been suggested that the PrP^Sc protein has more beta-strand content than the normal protein, but how this property would lead to prion replication was unknown. Clearly solving the structure of prion protein was needed to fully understand the biology of this unusual pathogen.

The structure of PrP^Sc protein has now been solved by cryo-electron microscopy and image reconstruction (link to paper). The protein was purified from transgenic mice programmed to produce a form of  PrP^Sc protein that is not anchored to the cell membrane, and which is also underglycosylated. The protein causes disease in mice but is more homogeneous and forms fibrillar plaques, allowing gentler purification methods.

The structure of this form of the PrP^Sc protein reveals that it consists of two intertwined fibrils (red in the image) which most likely consist of a series of repeated beta-strands, or rungs, called a beta-solenoid. The structure provides clues about how a pathogenic prion protein converts a normal PrP^C into PrP^Sc . The upper and lower rungs of beta-solenoids are likely the initiation points for hydrogen-bonding with new PrP^C molecules – in many proteins with beta-solenoids, they are blocked to prevent propagation of beta-sheets. Once added to the fibrils, the ends would serve to recruit additional proteins, and the chain lengthens.

The structure of PrP^Sc protein provides a mechanism for prion replication by incorporation of additional molecules into a growing beta-solenoid. I wonder if incorporation into fibrils is the sole driving force for converting PrP^Cprotein into PrP^Sc, or if PrP^C is conformationally altered before it ever encounters a growing fibril.

The TWiV team discusses eye infections caused by Zika virus, failure of Culex mosquitoes to transmit the virus, and replication of norovirus in stem cell derived enteroids.

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Professor Simon Gaskell
President and Principal
Queen Mary University of London
Mile End Road
London E1 4NS

Dear Professor Gaskell:

Last month, the First-Tier Tribunal ordered Queen Mary University of London to release critical data from the PACE trial of treatments for chronic fatigue syndrome, also known as myalgic encephalomyelitis, or ME/CFS. In its decision, which rejected the university’s appeal of last fall’s ruling from the Information Commissioner’s Office, the tribunal dismantled all of QMUL’s rationalizations for keeping the data secret.

In particular, the tribunal dismissed the fears of QMUL’s security expert that hostile patients would be able to de-anonymize the data in order to identify and harass trial participants. Such concerns, noted the tribunal, were “grossly exaggerated” and based on “a considerable amount of supposition and speculation with no actual evidence.” The tribunal also noted pointedly that the “seeming reluctance” of the PACE investigators “to engage with other academics they thought were seeking to challenge their findings” had strengthened the case for releasing the data publicly.

Significantly, the tribunal emphasized that criticism of the PACE trial was not limited to a small group of patients, citing the “impressive” roster of 42 scientists and clinicians who supported Virology Blog’s open letter of concern to The Lancet last February. The open letter was based on an investigative report about PACE by David Tuller, a lecturer in public health and journalism at the University of California, Berkeley; Virology Blog posted Dr. Tuller’s investigation last October. The letter outlined some of the study’s major deficiencies, declared that “such flaws have no place in published research,” and requested that The Lancet seek a fully independent analysis of the trial data. All of us signed or later endorsed that open letter.

The current case involves a freedom-of-information request filed by an Australian patient, Alem Matthees. The data he requested would allow for an independent analysis based on the primary outcome thresholds and the definition of “recovery” outlined in the published trial protocol. These promised results remain unknown, because the investigators dramatically changed their protocol methods of assessing the two primary measures of fatigue and physical function. They also relaxed all four criteria for determining “recovery”—so much so that participants could already be “recovered” at baseline on the two primary measures, before any treatment at all.

The investigators have refused to provide the results per the original methods established in the protocol. They have also not provided any sensitivity analyses to assess the impact of the mid-trial changes on the reported findings. This is unacceptable. It is also antithetical to good science and honest debate, as are the other flaws cited in the Virology Blog open letter and in Dr. Tuller’s investigation. (In fact, patients and advocates began pointing out the study’s problems years ago, but their legitimate concerns were consistently ignored, ridiculed or misrepresented.)

The PACE trial has greatly impacted policies and attitudes toward ME/CFS, popularizing the notion that psychotherapy and exercise are effective treatments. Yet patients routinely experience serious relapses after even minimal activity. A report last year from the Institute of Medicine called this phenomenon “exertion intolerance” and identified it as the defining symptom of the disease. This key IOM finding strongly suggests that to increase activity levels, as the PACE interventions recommend, is contraindicated and potentially harmful.

The PACE trial remains under an enormous cloud, and the requested data will provide answers to some of the questions. Given the tribunal’s powerful and persuasive rejection of QMUL’s arguments, prolonging the legal process will only further tarnish the university’s reputation, waste more public funds, and discourage others from participating in future QMUL-sponsored research—all for an indefensible and ultimately losing cause.

We strongly urge QMUL not to appeal the decision of the First-Tier Tribunal and to release the PACE trial data as soon as possible.

Sincerely–

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

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

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

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

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

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

Charles Shepherd, MB BS
Honorary Medical Adviser
ME Association
London, England

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

The TWiXers discuss a study on vertical transmission of Zika virus by Aedes mosquitoes, and uncovering Earth’s virome by mining existing metagenomic sequence data.

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By David Tuller, DrPH

In January, I posted a list of the questions I still wanted to ask the PACE authors, who have repeatedly refused my requests to interview them about their ethically and methodologically challenged study. Richard Horton, editor of The Lancet, has similarly declined to talk with me, ignoring my e-mails seeking comment for the initial investigation, posted on Virology Blog last October, as well as for several follow-up articles. Now Dr. Horton has doubled-down on his efforts to keep a lid on the controversy by rejecting a letter that he personally solicited—a major breach of professional courtesy to the 43 well-regarded researchers and clinicians who signed it.

As Dr. Racaniello explained this week at Virology Blog, he submitted the letter on behalf of the group in March, in response to an express invitation from Dr. Horton. The invitation came right after Virology Blog posted an open letter, based on my investigation, that outlined the trial’s major missteps. Dr. Racaniello presumed from the wording of Dr. Horton’s invitation that the letter would, in fact, be published, as did the other signatories. On Monday, having been dissed by The Lancet, Dr. Racaniello finally posted the letter on PubMed Commons. He also called the PACE trial “a sham.” (I’ve called it “a piece of crap.” I might also have referred to it somewhere as “doggie-poo,” but I’m not sure.)

In rejecting the letter that he himself solicited, Dr. Horton certainly appeared to be trying to squelch the growing public controversy over PACE and its recommendations that graded exercise therapy and cognitive behavior therapy are effective treatments for chronic fatigue syndrome (or myalgic encephalomyelitis, CFS, ME, CFS/ME, or ME/CFS, or some other name). But The Lancet’s effort to shield PACE is doomed, not only because the study is so bad but because the emerging science presents a completely different portrait of the illness. On Monday, a paper in Proceedings of the National Academy of Sciences reported distinct patterns of metabolites in the plasma of ME/CFS patients—an important finding that, if confirmed, could finally lead to diagnostic tests. The PNAS paper and other recent research support the conclusion of reports last year from both the Institute of Medicine and National Institutes of Health: ME/CFS is a devastating physiological disease.

Back in January, Columbia statistics professor Andrew Gelman blogged about the harm Dr. Horton was already inflicting on his journal by not addressing the serious questions that serious critics were raising about PACE. The longstanding claim of the PACE authors, The Lancet and the trial’s other defenders—that the opponents were a small cabal of irrational, dangerous, and anti-psychiatry patients—has been exposed as false. The PACE authors, The Lancet and their colleagues wielded this narrative for years to discredit those challenging the trial. To their dismay, this tactic is no longer working.

The Lancet’s decision to reject the Virology Blog letter will only compound the journal’s growing reputational damage over the issue. It also seems deeply short-sighted, in light of last month’s powerful court decision ordering Queen Mary University of London, the professional home of principal PACE investigator Peter White, to release the raw trial data. That would allow others to determine whether the PACE investigators altered their outcome assessments strategies to produce results more likely to get published in The Lancet and other journals. (The answer should not surprise anyone except those in extreme stages of denial.)

The decision involved a freedom-of-information request filed two years ago by Alem Matthees, an Australian patient. Since the published results did not include the results per the assessment methods outlined in the PACE trial protocol, Matthees wanted the data necessary to calculate those results for the two primary outcomes of fatigue and physical function, as well as for the original definition of “recovery.” Last October, the Information Commissioner’s Office, an independent agency, found that QMUL had no grounds for refusing to provide the data. QMUL appealed that ruling to the First-Tier Tribunal, which issued the recent decision.

The U.K. medical-academic-media establishment has wholly endorsed the PACE trial’s unreliable findings and accepted the authors’ unsubstantiated claims that they have been subjected to a concerted campaign of threats and harassment. In contrast, the tribunal demonstrated a refreshing unwillingness to play along. In robust language, the tribunal smacked down the specious arguments raised by the university in its attempt to shield the data from public disclosure.

The chance that any participant could or would be identified from the anonymized data was “remote,” the tribunal found. The scenarios envisioned ed by QMUL’s data security expert, who sketched out far-fetched strategies that “activist” patients might pursue to re-identify and then harass trial participants, were “grossly exaggerated” and “a considerable amount of supposition and speculation,” wrote the tribunal. In fact, noted the tribunal, the only incident of “harassment” proven by QMUL’s experienced legal team was that someone somewhere once heckled Trudie Chalder, a principal PACE investigator who also testified at the tribunal hearing. (I also have some thoughts on Dr. Chalder’s testimony, but will hold those for another time.)

In contrast to the QMUL portrait of PACE opponents, the tribunal cited Virology Blog’s open letter to The Lancet as evidence of a robust scientific debate, noting that “the identity of those questioning the research…was impressive.” The tribunal also noted that QMUL’s decision to share data with friendly researchers but not with others had created the impression that it was acting out of self-interest, not principle. “There is a strong public interest in releasing the data given the continued academic interest so long after the research was published and the seeming reluctance for Queen Mary University to engage with other academics they thought were seeking to challenge their findings,” declared the tribunal in the decision.

The PACE authors, QMUL, Dr. Horton, and The Lancet are stonewalling the obvious, at the expense of millions of sick patients. Although Dr. Horton will never grant me an interview, I want to highlight some of the questions I have about his actions, claims and thoughts, in case someone else gets the chance to talk with him. This list of questions is certainly not exhaustive, but it’s a decent start.

So, Dr. Horton–Here’s what I’d like to ask you:

1) Do you agree that the invitation you sent to Dr. Racaniello certainly implied, even if it didn’t explicitly promise, that The Lancet would publish the letter? Since the letter submitted by Dr. Racaniello, on behalf of himself and 42 other experts, reflected the points made in the Virology Blog open letter that triggered your invitation, what changed your mind about whether it added something to the debate? Since you personally solicited the letter from Dr. Racaniello and his colleagues, do you feel you should have sent him a personal apology, rather than leaving your correspondence editor, Audrey Ceschia, to answer for your behavior?

2) In your invitation to Dr. Racaniello, you noted that the PACE authors would have a chance to respond, alongside the published letter. That was a fair plan. When did that plan of offering them a response morph into the plan of offering them a role in discussions about whether to publish the critical letter in the first place? What impact did their views have on your decision? Did the PACE authors argue, as they have in the past, that they have already answered all these criticisms?

This repeated claim that they have answered all questions is simply untrue. They have never explained, for example, how it is possible to be disabled and “within normal range” on an indicator simultaneously, and why 13 % of their participants were already “within normal range” on one or both primary outcome sat baseline. When anyone asks legitimate questions, they evade, ignore or misstate the issues—including in the correspondence following The Lancet’s 2011 paper. (This pattern of non-response is clear from their non-responsive responses to the charges raised in my Virology Blog investigation, and my rebuttal of their non-responses.)

3) What’s your reaction to the First-Tier Tribunal’s decision ordering the release of the PACE trial data? Do you agree with the tribunal’s observation, referring to Virology Blog’s February open letter to you and The Lancet, that the roster of scientists and researchers now publicly questioning the methodology and findings of PACE is “impressive”?

4) Do think QMUL should spend more public money to appeal the decision?

If QMUL decides to appeal, do you think this will fuel the already-widespread assumption that PACE had null findings per the original protocol methods of assessment?

5) The PACE interventions, as described in The Lancet, are based on the premise that deconditioning rather than any pathological process perpetuates the illness, and that increased activity and a new psychological mind-set will fix the problem. The descriptions of the interventions categorically exclude the possibility of a continuing organic disease as the cause. Do you think this portrait of the illness squares with the view emerging from this week’s study in PNAS and other recent research, including last year’s reports from the Institute of Medicine and the National Institutes of Health?

6) The IOM report identified “exertion intolerance”—the prolonged relapses patients often suffer after minimal activity–as the core symptom of the illness. Yet a key aspect of the PACE rehabilitative interventions, GET and CBT, is urging patients to increase their activity and to interpret a resurgence of symptoms as a transient event, not a sign of deterioration. Given the IOM’s focus on “exertion intolerance” as the central phenomenon, isn’t the PACE approach contraindicated?

7) Does it bother you that you published a paper in which 13% of the sample had already, at baseline, met the outcome thresholds for one or both primary measures? These outcome thresholds, which represented worse health than the entry criteria, were variously defined as being “within normal range” (the Lancet paper), “back to normal” (Dr. Chalder’s statement at the press conference for the Lancet paper), and “a strict criterion for recovery” (the Lancet commentary by colleagues of the PACE authors). Can you point me to any other studies published in The Lancet, or anywhere, in which positive outcome scores represented worse health than entry criteria?

8) Does it bother you personally that the PACE authors did not inform you or your editorial staff that a significant minority of patients were already “within normal range” on at least one primary outcome at baseline? (I presume they didn’t mention it to you because, well, it’s hard to imagine you would have published the paper if you or anyone there had been told about or noticed the inexplicable overlap in the entry criteria and the post-hoc “normal range” thresholds.)

9) During a 2011 Australian radio interview not long after The Lancet published the first PACE results, you said the following about the trial’s critics: “One sees a fairly small, but highly organised, very vocal and very damaging group of individuals who have I would say actually hijacked this agenda and distorted the debate so that it actually harms the overwhelming majority of patients.” Given that the First-Tier Tribunal expressed a different perspective on the stature and credibility of those criticizing PACE, do you still agree with your 2011 characterization of the trial’s opponents?

10) During the same interview, you stated that the PACE trial had undergone “endless rounds of peer review.” Yet the trial was also “fast-tracked” to publication, as indicated on the version of the article in the ScienceDirect database. Can you explain the mechanics of “fast-tracking” a paper to publication while simultaneously subjecting it to “endless rounds of peer review”? How long was the fast-track process for the PACE paper, and how many actual rounds of review did the paper undergo during that endless period?

11) Can you explain why the Lancet’s endless peer review process did not catch the most criticized aspect of the paper—the very obvious fact that participants could be simultaneously disabled enough for entry yet already “within normal range”/”back to normal”/”recovered” on the primary outcomes? Can you explain why the reviewers did not request the authors to provide either the original results promised in the protocol or else sensitivity analyses to assess the impact of the mid-trial changes they introduced?

12) Do you think it was appropriate for the PACE investigators to publish a mid-trial newsletter that promoted the therapies under study and included glowing testimonials from earlier participants about their excellent outcomes? Can you point to other published studies that featured such mid-trial dissemination of personal testimonials and explicit descriptions of outcomes? The PACE authors have stated that the newsletter testimonials did not identify participants’ trial arms and therefore could not have created any bias. Do you agree with this novel and creative argument that influencing all remaining participants in a trial in a positive direction is not a form of bias?

13) Did The Lancet’s peer review process include an evaluation of the PACE trial’s consent forms, given the authors’ explicit promise in the protocol to abide by the Declaration of Helsinki? The Declaration of Helsinki requires investigators to disclose “any possible conflicts of interest” not just to journals but to prospective participants. Yet the PACE consent forms did not disclose the authors’ close financial and consulting ties with the insurance industry. Do you agree this omission violates their protocol promise, and that given this violation the PACE authors failed to obtain legitimate informed consent from their participants? Without legitimate informed consent, did the PACE authors have the right to publish their findings in The Lancet and other journals? What should happen to the PACE papers already published, since the authors do not appear to have legitimate informed consent from participants?

14) Who do you think should be held responsible for the $8,000,000 in U.K. government funds wasted on the PACE trial? Who should be held responsible for the harm it has caused? What responsibility, if any, does The Lancet bear for the debacle?

Last February, Virology Blog posted an open letter to The Lancet and its editor, Dr. Richard Horton, describing the indefensible flaws of the PACE trial of treatments for ME/CFS, the disease otherwise known as chronic fatigue syndrome (link to letter). Forty-two well-regarded scientists, academics and clinicians put their names to the letter, which declared flatly that the flaws in PACE “have no place in published research.” The letter called for a completely independent re-analysis of the PACE trial data, since the authors have refused to publish the results they outlined in their original protocol. The letter was also sent directly to Dr. Horton.

The open letter was based on the extensive investigative report written by David Tuller, the academic coordinator of UC Berkeley’s joint program in journalism and public health, which Virology Blog posted last October (link to report). This report outlines such egregious failings as outcome thresholds that overlapped with entry criteria, mid-trial promotion of the therapies under investigation, failure to provide the original results as outlined in the protocol, failure to adhere to a specific promise in the protocol to inform participants about the investigators’ conflicts of interest, and other serious lapses.

Virology Blog first posted the open letter in November, with six signatories (link to letter). At that time, Dr. Horton’s office responded that he would reply after returning from “traveling.” Three months later, we still had not heard back from Dr. Horton–perhaps he was still “traveling”–so we decided to republish it with many more people signed on.

The day the second open letter was posted, Dr Horton e-mailed me and solicited a letter from the group. (He did not explain where he had been “traveling” for the previous three months.) Here’s what he wrote: “Many thanks for your email. In the interests of transparency, I would like to invite you to submit a letter for publication–please keep your letter to around 500 words. We will then invite the authors of the study to reply to your very serious allegations.”

Dr. Horton’s e-mail clearly indicated that the letter would be published, with the PACE authors’ response to the charges raised; there was no equivocation or possibility of misinterpretation. In good faith, we submitted a letter for publication the following month, with 43 signatories this time, through The Lancet’s online editorial system (see the end of this article for a list of those who signed the letter). After several months with no response, we learned only recently by checking the online editorial system that The Lancet had flatly rejected the letter, with no explanation. No one contacted me to explain the decision or why we were asked to spend time creating a letter that The Lancet clearly had no intention of publishing.

I wrote back to Dr. Horton, pointing out that his behavior was highly unprofessional and requesting an explanation for the rejection. I also asked him if he was in the habit of soliciting letters from busy scientists and researchers that his journal had no actual interest in publishing. I further asked if the journal planned to reconsider this rejection, in light of the recent First-Tier Tribunal decision, which demolished the PACE authors’ bogus reasons for refusing to provide data for independent analysis.

Dr. Horton did not himself apologize or even deign to respond. Instead, Audrey Ceschia, the Lancet’s correspondence editor, replied, explaining that the Lancet editorial staff decided, after discussing the matter with the PACE authors, that the letter did not add anything substantially new to the discussion. She assured us that if we submitted another letter focused on the First-Tier Tribunal decision, it would be “seriously” considered. I’m not sure why she or Dr. Horton think that any such assurance from The Lancet is credible at this point.

The reasons given for the rejection are clearly specious. The letter for publication reflected the matters addressed in the open letter that prompted Dr. Horton’s invitation in the first place, and closely adhered to his directive  to outline our “serious allegations”. If outlining these allegations was not considered publication-worthy by The Lancet, it is incomprehensible to us why Dr. Horton solicited the letter in the first place. Perhaps it was just an effort to hold off further criticism for a period of months while we awaited publication of the letter, unaware of the journal’s intention to reject it. It is certainly surprising that The Lancet appears to have given the PACE authors some power to determine what letters appear in the journal itself.

Dr. Tuller’s investigation, based on the groundbreaking analyses conducted by many savvy patients and advocates since The Lancet published the first PACE results in 2011, has effectively demolished the credibility of the findings. So has a follow-up analysis by Dr. Rebecca Goldin, a math professor at George Mason University and director of Stats.org, a think tank co-sponsored by the American Statistical Association. In short, the PACE study is a sham, with meaningless results. In this case, the emperor truly has no clothes. Dr. Horton and his editorial team at The Lancet are stark naked.

Yet the PACE study remains in the literature. Its recommendation of treatments that are potentially harmful to patients–specifically, graded exercise therapy and cognitive behavior therapy, both designed specifically to increase patients’ activity levels–remains highly influential.

Of particular concern, the PACE findings have laid the groundwork for the MAGENTA study, a so-called “PACE for kids” that will be testing graded exercise therapy in children and adolescents. A feasibility study, sponsored by Royal United Hospitals Bath NHS Foundation Trust, is currently recruiting participants. It is, of course, completely unacceptable that any study should justify itself based on the uninterpretable findings of the PACE trial. The MAGENTA trial should be halted until the PACE authors have done what the First-Tier Tribunal ordered them to do–release their raw data and allow others to analyze it according to the outcomes specified in the PACE trial protocol.