March 22, 2018

expert reaction to reanalysis of the PACE trial for chronic fatigue syndrome (CFS) treatments

A reanalysis of the PACE trial is published in BMC Psychology.

A Before the Headlines analysis accompanied this roundup.

Dr Jon Stone, Consultant Neurologist and Honorary Senior Lecturer, Western General Hospital, Edinburgh, said:

“This reanalysis of data from the PACE trial shows that using more stringent outcome measures, patients with CFS/ME had a better outcome at one year with Cognitive Behavioural Therapy(CBT), Graded Exercise Therapy (GET) than the control group, but the proportion improved was not as large as in the original report (20%/21% vs 10% in this reanalysis). This is not a surprising result. That would be the expected effect of using more restrictive criteria in any similar trial. The apparent benefit will be reduced for those undergoing the intervention, and also for the controls.

“Has CBT and GET been oversold for CFS/ME? There is no doubt we need better treatments. They only have a modest treatment effect overall and are certainly not suitable for all patients with the condition. The evidence that these treatments lead to a better outcome than controls at 2.5 years is also lacking, both from the studies original authors and from this analysis. But that is because the trial only lasted one year. Cohort data and the post-hoc subgroup analysis in this reanalysis can’t be used to resolve that issue, but does at least provide evidence that benefit in the CBT/GET groups was sustained, even if the other groups subsequently caught up.

“One of the assertions of this reanalysis, that treatment effects seen may simply be the result of unblinded self-report measures, would not explain why patients undergoing adaptive pacing therapy (APT) did worse than those receiving CBT and GET in the original study who were also unblinded to therapy. It is disappointing that the pacing therapy data was not reanalysed as part of this study.

“We need better treatments for CFS/ME, be they biological treatments directed at the associated pathophysiology of the condition, or more effective forms of rehabilitation. Until we have these, the question is whether it is better to offer a modestly effective treatment supported by data from many other trials, with a realistic discussion of its pros and cons, than none at all.

“The PACE Trial has been subject to an extraordinary degree of hostility. On the basis of this reanalysis, this was not warranted – the basic difference in outcomes are still present.  Additionally, it is worth reflecting that positive trials of CBT for fatigue in conditions such as Multiple Sclerosis with similar treatment effects do not mean that MS is a psychological condition. The same is true for CBT/GET and CFS/ME.”

Prof Chris Ponting, Professor of Medical Bioinformatics, University of Edinburgh, said:

“In 2011 the PACE group interpreted their randomised trial data to mean that cognitive behaviour therapy (CBT) and graded exercise therapy (GET) “can safely be added to [specialist medical care] to moderately improve outcomes for chronic fatigue syndrome [CFS, or M.E./CFS]”. Now Wilshire and coauthors report on a new analysis of the PACE trial’s data. This reanalysis was required in part because the trial group had revised their analysis from the plan published in their protocol. This revision meant that, in theory, some trial participants nonsensically could be accepted on to the trial as patients, yet then be considered to have recovered by the trial’s end despite their symptoms not improving, or even deteriorating. Wilshire et al. provide evidence that “the effects of CBT and GET were very modest – and not statistically reliable overall if we apply procedures very close to those specified in the original published protocol”. Their analysis also revealed that recovery rates according to the protocol definition were much lower than previously published and that CBT and GET did not lead to recovery.

Importantly, Wilshire et al. provide a plausible explanation even of these modest effects. Specifically, they argue that they are explicable simply from the raised expectations of CBT and/or GET participants that their treatments would be effective. Expectations are heightened, they argue, when participants are not blinded to their treatment and are assured that their treatment is effective, as was the case for the PACE trial. The absence of meaningful gains in objective outcome measures such as fitness indicates that gains on self-report measures may well be unreliable.  This could largely explain both the modest effects seen after 1 year and the disappearance of these effects subsequently. The authors also make the case that the lack of substantial and enduring effects of CBT and/or GET seen from a trial of the size of PACE implies that these therapies are unlikely to be commonly effective.”

Comment from three authors of the original PACE trial

Prof Michael Sharpe, Professor of Psychological Medicine, University of Oxford, Prof Trudie Chalder, Professor of Cognitive Behavioural Psychotherapy, Institute of Psychiatry Psychology & Neuroscience (IoPPN), King’s College London, & Dr Kimberley Goldsmith Senior Lecturer in Medical Statistics, Institute of Psychiatry Psychology & Neuroscience (IoPPN), King’s College London, said:

“Wilshire et al have written a critique of several papers reporting on the PACE trial of treatments for CFS/ME, of which we are authors.  They also report a reanalysis of the PACE trial data.  We note that most of the analyses they report have already been published, either in peer reviewed journals or by ourselves on the PACE trial website (https://www.qmul.ac.uk/wolfson/research-projects-a-z/current-projects/pace-trial/).

“They report different results from the original trial. However this is not surprising as their analyses used only part of the trial dataset and followed a preliminary PACE analysis plan, rather than the final approved and published one. Furthermore they do not refer to the many other trials and meta-analyses that have replicated the findings of the PACE trial.

“In conclusion we find little of substance in this critique and stand by our original reports. These are all available through the trial website (see above). The PACE trial found that CBT and graded exercise therapy are safe and moderately effective treatments; a positive message for people who suffer from this otherwise long-term debilitating illness.”

* ‘Rethinking the treatment of chronic fatigue syndrome—a reanalysis and evaluation of findings from a recent major trial of graded exercise and CBT’ by Wiltshire et al. published in BMC Psychology on Thursday 22 March.

All our previous output on this subject can be seen at this weblink: http://www.sciencemediacentre.org/?s=CHRONIC%20FATIGUE%20SYNDROME&cat

The SMC also produced a Factsheet on CFS/ME which is attached and available here: http://www.sciencemediacentre.org/cfsme-the-illness-and-the-controversy/

Declared interests

Dr Jon Stone: “Prof Sharpe was my PhD supervisor in 2003. I do collaborate with Trudie Chalder on another RCT (www.codestrial.org) and have invited her to conferences etc. I still co-author some publications with Michael as well.”

Prof Chris Ponting: “I have no conflicts of interest.”

Prof Michael Sharpe, Prof Trudie Chalder & Dr Kimberley Goldsmith: Profs Sharpe, Prof Chalder, and Dr Goldsmith are all authors on the original PACE trial. Prof Chalder is an author of self-help books on CFS.