On 28th October 2015 ‘Lancet Psychiatry’ published a report of the follow-up of the highly controversial PACE Trial
The ME Association immediately made the this press release (click here) standing by it’s criticism of both the PACE Trial and the use of GET ang CBT as treatments for ME/CFS. It also metioned it’s own study which found that 70% of people with ME/CFS found GET made their symptoms worse.
Some of the obvious flaws and problems of the trial were:
- Lack of blinding
- Exclusion of housebound/bedbound patients.
- Use of the Oxford criteria for ME/CFS which is very different the International Consensus Criteria and would include a far larger cohort and possible none of those meeting the ICC.
- The baseline criteria for inclusion in the study actually indicated better health – in terms of fatigue and physical function – than the benchmark for “recovery” at the end. In other words, a patient could be simultaneously sick enough to be included in the PACE study, and healthy enough to be counted among the positive outcomes.
- Participants who were assigned to graded exercise walked fewer meters in six minutes than patients with pacemakers, patients with class II heart failure, and cystic fibrosis patients – a level of function they defined as “recovery.”
This would appear to invalidate the trials claims that 30% of participants had recovered.
For more technical critique of the PACE trial see below:
Jonathan Edwards, Professor Emeritus, Dept Medicine, University College London says:
I would like to put on record a summary of the reasons why I think the PACE trial is valueless, in the light of the recent follow up publication. I am happy to have this summary quoted or reproduced in any public medium.
PACE is valueless for one reason: the combination of lack of blinding of treatments and choice of subjective primary endpoint. Neither of these alone need be a fatal design flaw but the combination is.
The only possible mitigation of this flaw would be if:
1. There were no acceptable alternatives to a subjective primary outcome measure, and
2. The authors fully understood the nature of the flaw and the reasons why it is so serious, and
3. The authors were meticulous in trying to avoid all forms of bias that are likely to arise from the flaw.
It has been apparent from the outset that alternative objective endpoints were available. These might not be ideal in a blinded study (the blinded Norwegian rituximab study chose a subjective end point for preference) but an objective primary endpoint would have been practical. The objective endpoints in PACE used as secondary measures tended to show no difference in outcome.
The authors (and colleagues) have repeatedly indicated in public that they do not understand the flaw in the PACE trial design, as made clear by claims that the study is ‘robust’ and of high design quality. Moreover, the authors have not been meticulous in trying to avoid bias that might arise. On the contrary they appear to have acted in ways more or less guaranteed to maximise bias. (The details are well documented but are secondary to the main problem.)
The recent follow up study may be of some use in confirming the sensible conclusion to draw from the objective measures used in PACE – that it provides no evidence for any benefit from CBT or GET. It strengthens the case by suggesting that at longer term follow up even the subjective measure differences disappear. It also highlights again the authors’ lack of understanding of trial design problems. Moreover, as outlined by Dr James Coyne, it provides further evidence for the authors’ tendency to continually introduce bias in their analysis, apparently through a lack of understanding of basic data interpretation and statistics. One might expect errors of this sort from a clinical trainee, but not from a professional research team.
I am surprised and troubled that clinical and research colleagues in the ME/CFS field have said so little about the problems with this study. It has been left to David Tuller and James Coyne to raise the issue again. Regardless of other issues relating to the illness (that have been grossly misrepresented in the popular media recently) it needs to be recognised and agreed that the PACE study is not a suitable evidence base for clinical practice guidelines.
Jo Edwards. Professor Emeritus, Dept Medicine, UCL
Dr Neil Abbott (ME Research UK):
This story is no more than spin, based on an over-hyped press release.
In fact, the actual scientific paper reports on a postal survey of ME/CFS patients, 30 months after they took part in a large-scale clinical study (the PACE trial) comparing cognitive behavioural or graded exercise therapy with standard medical care or activity pacing.
The real findings are unremarkable; as the authors themselves say, “There was little evidence of differences between the four groups in fatigue or in physical functioning at long-term follow-up”.
The authors may speculate that patients in the standard medical care or pacing exercise groups were ‘helped’ by additional psychological therapies in the 18 months after the end of the trial, but they don’t know that for certain, and nor do they show data to back up their claim. The reductions in symptoms could equally well be due to improvements in the illness over time; to the long-term effects of the standard medical care or activity pacing; or to a range of other factors.
We need to get past the hype, and look at the real problems facing the research and treatment of people with ME/CFS.
First, clarify diagnosis; we know that 40% of patients referred to clinics with ME/CFS are eventually diagnosed with another disease – so proper clinical-evaluation-based diagnosis (including the exclusion of other disorders) is urgently needed (http://bit.ly/1ki4MkV).
Second, put psychology in perspective; we know that psychological therapies help some people cope with chronic illnesses like cancer and MS but we recognise that they are not specific treatments and are certainly not curative – there is now ample evidence that the same is also true for ME/CFS, and healthcare professionals everywhere need to accept the fact (http://bit.ly/1jReUao).
Third, beef up the science; with psychology in its proper place, biomedical investigation (and funding) should focus on developing and using all the tools in the clinical and therapeutic armoury needed to treat and (ultimately) cure the underlying disease.
Dr Neil Abbot, ME Research UK