A Special issue of Journal of Health Psychology concerns PACE, a trial of therapies for patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) that has attracted a great deal of controversy
Key points summarized from the David F. Marks’ introductory editorial
The idea for Special Issue started with Journal of Health Psychology receiving a manuscript from Keith Geraghty providing a critical review of the PACE Trial.
Following peer review and acceptance of a revision, the PACE investigators were offered an opportunity to respond to Keith Geraghty with an Open Peer Commentary paper.
The PACE investigators made a number of efforts to get Geraghty’s article outright retracted, either directly or through pressures on the editorial board.
When it was clear that the journal would not cave to such pressures, the PACE investigators then demanded a partial retraction of the Geraghty article and that the journal issue a correction reporting that the author had an undisclosed conflict of interest: he had failed to acknowledge that he was a patient suffering from myalgic encephalomyelitis.
The PACE investigators also demanded that their commentary manuscript will not be subject to peer review.
The PACE investigators received reviews of their manuscript. Editor Marks notes [Having been involved in editing this issue, I agree]:
After receiving critical reviews, the pro-PACE authors chose to make only cosmetic changesor not to revise their manuscripts in any way whatsoever. They appeared unwilling to enter into the spirit of scientific debate. They acted with a sense of entitlement not to have to respond to criticism.
The review and response from the PACE investigators was sent to more than 40 experts on both sides of the debate for commentaries.
After the online publication of several critical Commentaries, the PACE investigators were offered a further opportunity to respond to their critics in the round but they chose not to do so. There was little response, but a notable declining of further comment by the PACE investigastors:
As always, we would refer interested readers to our original publications and trial websitewhere most, if not all, the issues brought up by commentators are addressed
Conflict of interest.
[My comment: The PACE investigators and persons associated with them were quick to complain about the conflict of interest in the developing issie. As noted, this including a complaint about Geraghtybeing a patient and not disclosing it, mentioned above. But the investigators also threatened a formal complaint to the Committee on Publication Ethics concerning my having reviewed their manuscript. But there is an ironic backstory about the matter of conflict of interest. Some of which are discussed in contributions to the Special Issue:]
The PACE authors themselves appear to hold strong allegiances to cognitive behavioural therapy (CBT) and graded exercise therapy (GET) – treatments they developed for ME/CFS. Stark COI have been exposed by the commentaries including the PACE authors themselves who hold a double role as advisers to the UK Government.
Department of Work and Pensions (DWP), a sponsor of PACE, while at the same time working as advisers to large insurance companies who have gone on record about thepotential financial losses from ME/CFS being deemed a long-term physical illness.In a further twist to the debate, undeclared COI of Petrie and Weinman (2017) werealleged by two of the commentators (Agardy, 2017; Lubet, 2017). Professors Weinman andPetrie adamantly deny that their work as advisers to Atlantis Healthcare represents a COI.
[My comment: In another instance, three pro-PACE authors attempted to subvert the journal’s policy on COI by recommending reviewers who were strongly conflicted, forcing rejection of their paper. I discussed this in another blog post.]
[My comment: Nonetheless, having gotten any commentary from the PACE investigators at all was an achievement. Even the limited responsiveness of the PACE investigators to Geraghty’s commentary, along with a supported commentary by their close colleagues Keith J Petrie and John Weinman, the special issue represents one of most significant exchanges between defenders of the PACE trial and critics in a long while.]
ME/CFS research has been poorly served by the PACE Trial and a fresh new approach is needed by the PACE investigators to engage critics and skeptics.
Overall, the special issue provides, readers to make up their own minds about the scientific merits and demerits of the PACE Trial.
Note that the entire Special Issue is available with free access.
The individual papers
‘PACE-Gate’: When clinical trial evidence meets open data access. Keith J Geraghty
Published reports of the PACE trial overstated the effectiveness of cognitive behavioural therapy and graded exercise therapy, and did so by lowering the thresholds they used to determine improvement. Reanalyzes conducted by professionals and patients revealed that the treatments tested had much lower efficacy after an information tribunal ordered the release of data from the PACE trial to a patient who had requested access using a freedom of information request.
Response to the editorial by Dr Geraghty. Peter D White, Trudie Chalder, Michael Sharpe, Brian J Angus, Hannah L Baber, Jessica Bavinton, Mary Burgess, Lucy V Clark, Diane L Cox, Julia C DeCesare, Kimberley A Goldsmith, Anthony L Johnson, Paul McCrone, Gabrielle Murphy, Maurice Murphy, Hazel O’Dowd, Laura Potts, Rebacca Walwyn and David Wilks
The trial found that adding cognitive behavior therapy or graded exercise therapy to specialist medical care was as safe as, and more effective than, adding adaptive pacing therapy or specialist medical care alone. Dr Geraghty has challenged these findings. We suggest that Dr Geraghty’s views are based on misunderstandings and misrepresentations of the PACE trial.
This commentary examines how the current response once again demonstrates the ways in which the investigators avoid acknowledging the obvious problems with PACE and offer non-answers instead—arguments that fall apart quickly under scrutiny.
Investigator bias and the PACE trial. Steven Lubet
Standards for determining researcher bias are considered and it is concluded that the PACE nvestigators’ impartiality might reasonably be questioned.
In the PACE trial, cognitive behavioural therapy and graded exercise therapy had modest, time-limited effects trial on self-report measures, but little effect on more objective measures such as fitness and employment status. In non-blinded trials, the issue of reporting biases deserves greater attention in future.
Protocols and outcomes for the PACE trial were changed after the start of the trial, leading to exaggerated claims for the efficacy for both cognitive behavior therapy and graded exercise therapy. Findings of small, self-reported improvements in subjective measures cannot be used to say the interventions are effective, particularly in light of the absence of objective improvements with objective outcome measures.
The PACE trial missteps on pacing and patient selection. Leonard A Jason
The PACE trial investigators were not successful in designing and implementing a valid pacing intervention and patient selection ambiguity further compromised the study’s outcomes
The trial’s poor results on objective measures of fitness suggest a lack of adherence to the activity component of these therapies. Therefore, the safety findings may not apply in other clinical contexts. Outside of clinical trials, many patients report deterioration with cognitive behavioural therapy and particularly graded exercise therapy. Also, exercise physiology studies reveal abnormalities in chronic fatigue syndrome patients’ responses to exertion. Given these considerations, one cannot conclude that these interventions are safe and risk-free.
PACE team response shows a disregard for the principles of science. Jonathan Edwards
The response by White et al. fails to address the key design flaw, of an unblinded study with subjective outcome measures, apparently demonstrating a lack of understanding of basic trial design requirements. The failure of the academic community to recognise the weakness of trials of this type suggests that a major overhaul of quality control is needed.
Bias, misleading information and lack of respect for alternative views have distorted perceptions of myalgic encephalomyelitis/chronic fatigue syndrome and its treatment. Ellen Goudsmit and Sandra Howes
These interventions delivered in the PACE trial are based on a model which assumes that symptoms are perpetuated by factors such as misguided beliefs and a lack of activity. Our analysis indicates that the researchers have shown significant bias in their accounts of the literature and may also have overstated the effectiveness of the above treatments. We submit that their approach to criticisms undermines the scientific process and is inconsistent with best practice.
A review of survey data published between 2001 and 2015 reveals that for most patients, graded exercise therapy leads to worsening of symptoms, cognitive behavioural therapy leads to no change in symptoms, and pacing leads to improvement. The experience of people with ME/CFS as reflected in surveys is a rich source of information, made more compelling by the consistency of results. Consequently, patient survey evidence can be used to inform practice, research and guidelines. Misrepresentation of patient experience must be vigorously challenged, to ensure that patients and health professionals make decisions about therapies based on accurate information.