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PACE Trial and PACE Trial Protocol

Dolphin

Senior Member
Messages
17,567
From: PubMed Commons
http://www.ncbi.nlm.nih.gov/pubmed/23363640#cm23363640_14248

Sam Carter2016 Feb 15 5:23 p.m. (58 minutes ago)

Exploring changes to PACE trial outcome measures using anonymised data from the FINE trial.
When the results of the PACE trial were published (1, 2) it was noted that the primary outcome measures and the definition of "recovery" described in the trial's published protocol (3) had been abandoned and replaced with markedly less stringent criteria.

The fully anonymised data set from the FINE trial(4), considered to be the PACE trial's "sister" study, makes it possible to explore how these changes may have affected the reported efficacy of the PACE trial's interventions.

At week 20 (assessment 2), 18 FINE trial participants met PACE trial post-hoc recovery thresholds (SF36 PF ≥ 60 and CFQ Likert ≤ 18) compared to only 3 participants who met the stricter, protocol-defined recovery thresholds (SF36 PF ≥ 85 and CFQ bimodal ≤ 3). Therefore, at assessment 2, the post-hoc changes increased the "recovery" rate by a factor of 6.

By week 70 (assessment 3), between 10 and 12 of the original 18 had relapsed so that they no longer met the post-hoc recovery thresholds (data are missing for two participants). Such a high rate of relapse within a year shows that the post-hoc recovery thresholds, said to represent a "strict criterion for recovery" in a Comment (5) which accompanied the original publication of PACE trial results, are neither strict nor reliable indicators of sustained wellbeing.

Regarding the Chalder fatigue questionnaire, White et al wrote that "we changed the original bimodal scoring of the Chalder fatigue questionnaire (range 0–11) to Likert scoring to more sensitively test our hypotheses of effectiveness" (1). However, data from the FINE trial show that Likert and bimodal scores are often contradictory and thus call into question White et al's assumption that Likert scoring is necessarily more sensitive than bimodal scoring.

For example, of the 33 FINE trial participants who met the post-hoc PACE trial recovery threshold for fatigue at week 20 (Likert CFQ score ≤ 18), 10 had a bimodal CFQ score ≥ 6 so would still be fatigued enough to enter the PACE trial and 16 had a bimodal CFQ score ≥ 4 which is the accepted definition of abnormal fatigue.

Therefore, for this cohort, if a person met the PACE trial post-hoc recovery threshold for fatigue at week 20 they had approximately a 50% chance of still having abnormal levels of fatigue and a 30% chance of being fatigued enough to enter the PACE trial.

A further problem with the Chalder fatigue questionnaire is illustrated by the observation that the bimodal score and Likert score of 10 participants moved in opposite directions at consecutive assessments i.e. one scoring system
showed improvement whilst the other showed deterioration.

Moreover, it can be seen that some FINE trial participants were confused by the wording of the questionnaire itself. For example, a healthy person should have a Likert score of 11 out of 33, yet 17 participants recorded a Likert CFQ score of 10 or less at some point (i.e. they reported less fatigue than a healthy person), and 5 participants recorded a Likert CFQ score of 0.

The discordance between Likert and bimodal scores and the marked increase in those meeting post-hoc recovery thresholds suggest that White et al's deviation from their protocol-specified analysis is likely to have profoundly affected the reported efficacy of the PACE trial interventions.

An independent re-analysis of anonymised PACE trial data as described in its published protocol is urgently required to quantify the effects of the revised outcome and recovery criteria.

References

(1) White PD et al (2011) Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue syndrome (PACE): a randomised trial. Lancet Mar 5;377(9768):823-36.
(2) White PD, Goldsmith K, Johnson AL, Chalder T, Sharpe M (2013) Recovery from chronic fatigue syndrome after treatments given in the PACE trial. Psychol Med. Oct;43(10):2227-35.
(3) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R (2007) Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive behaviour therapy, and graded exercise, as supplements to standardised specialist medical care versus standardised specialist medical care alone for patients with the chronic fatigue syndrome/myalgic encephalomyelitis or encephalopathy. BMC Neurol Mar 8;7:6.
(4) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685991/bin/pone.0144623.s002.dta
(5) Bleijenberg G, Knoop H. (2011) Chronic fatigue syndrome: where to PACE from here? Lancet. Mar 5;377(9768):786-8.
 

Tom Kindlon

Senior Member
Messages
1,734
Title: As major medical journals balk, BMJ moves forward with routine data sharing"
by
James Coyne Ph.D

http://bit.ly/1VvasL3
i.e.
https://jcoynester.wordpress.com/20...bmj-moving-forward-with-routine-data-sharing/

Extracts:

Over time, I’ve gotten to know some of the individuals who have previously requested data, although I have never met them. They impress me as amply qualified to analyze data, and they often analyze data that I report in my blogs, with them asking for no credit. Many of them have been academics or have had other professional achievements. Others were progressing well along in their educational pathways before they were struck by their illness. Still others become citizen-scientists with the capacity to publish peer reviewed letters to the editor as a result of struggling to deal with their misunderstood medical condition.

There is something ugly, pernicious going on here, more fundamental than the question of data sharing. Being a patient with chronic fatigue syndrome/ myalgic encephalomyelitis is what sociologists like Erving Goffman would call a spoiled identity . Being a patient means being stripped of all other significant social identities and being reduced to a common denominator, stigmatized role.

Long after the current crisis about data sharing is resolved, issues about respect for patients that have been uncovered in the UK will remain. These issues are shocking to outsiders. In the United States, they would variously framed as discrimination and even human rights issues. I wouldn’t be surprised if there is not some movement in the UK to identify these issues in the same terms.

But there is also an affront to any conception of patient empowerment.
After all, the PACE investigators are making claims that have profound implications for the treatment and well-being of patients.

[..]

Thornton S. Beyond rhetoric: we need a strategy for patient involvement in the health service. BMJ. 2014 Jun 23;348:g4072.
[http://www.bmj.com/content/348/bmj.g4072.short]

"UK government is heavy on the hyperbole of empowering patients but lacks a robust strategy.

Respect for a patient’s individual autonomy is an accepted principle in modern medicine. In the past half century, the concept of autonomy has usurped medical paternalism in almost all of its forms and has aspired to promote patients from passive recipients of care to partners in planning their own treatment.1 Now the concept has extended beyond individual autonomy to an expectation of empowerment at the population level."

But the editorial clearly puts the issue on the table in a way that is in sharp contradiction to the way patients are being treated by Peter White and the PACE investigators.
Phoenix Rising thread:
http://forums.phoenixrising.me/inde...oves-forward-with-routine-data-sharing.43175/
 

Dolphin

Senior Member
Messages
17,567
In this new CDC paper:
Unger ER1, Lin JM1, Tian H1, Gurbaxani BM1, Boneva RS1, Jones JF1. Methods of applying the 1994 case definition of chronic fatigue syndrome - impact on classification and observed illness characteristics. Popul Health Metr. 2016 Mar 12;14:5. doi: 10.1186/s12963-016-0077-1. eCollection 2016.
http://pophealthmetrics.biomedcentral.com/articles/10.1186/s12963-016-0077-1
there is a CFS group with a mean SF-36 physical functioning score of 78.67. (This is taken from the table 4 data)

This is not with a unusual definition for CFS but the CFS (Fukuda et al., 1994) group that does not also satisfy the empiric criteria (Reeves et al 2005). In some ways one can't get any more mainstream.


People will recall that in the PACE Trial, one was considered having a normal physical function score if one scored 60 or more (similarly one could be recovered with a score of 60 or more).

Also only 20% of this group had a SF-36 physical function score of 70 or less.

Overall in the whole CFS sample, not just the Fukuda et al. (1994) group, 43% (37/86) had a SF-36 physical function score of more than 70. (This is calculated using the table 5 data)
 
Last edited:

Tom Kindlon

Senior Member
Messages
1,734
James Coyne has just written a blog challenging part of the response by Lillebeth Larun to my comments:
Why the Cochrane Collaboration needs to clean up conflicts of interest
https://jcoynester.wordpress.com/20...tion-needs-to-clean-up-conflicts-of-interest/
He picks up on the part where she claims their PACE trial should be assessed as having a "low-risk" of bias.

Phoenix Rising thread on the blog is here:
http://forums.phoenixrising.me/inde...icts-of-interest-on-get-for-cfs-review.43690/
 

Dolphin

Senior Member
Messages
17,567
Via @maxwhd on Twitter

http://www.icr-global.org/community/forums/ethics-gcp-forum/

Ethics & GCP Forum
Overview
The ICR Ethics and GCP Forum provides an excellent opportunity to:

  • Keep up to date with current ethical and clinical research issues
  • Learn about new industry and regulatory initiatives
  • Hear key industry figures speak about their specialist fields
  • Network with fellow clinical research professionals
[..]


13:45 Clinical Trial Controversies – the challenge of the PACE study, Trudie Chalder, Kings College London
 

Dolphin

Senior Member
Messages
17,567

Cheshire

Senior Member
Messages
1,129
Debate over Chronic Fatigue Syndrome Therapy
By Jane Collingwood

http://psychcentral.com/news/2016/04/05/debate-over-chronic-fatigue-syndrome-therapy/101259.html

Well, it adds nothing to the debate... A tribune to the usual spin by Sharpe and White, with a counter view from @charles shepherd, but the article is writen in a way that clearly favors BPS option.

Example
However, the conclusions reached by the study’s authors have been criticized because long-term improvements were similar over the four groups, perhaps because a large proportion of participants in the adaptive pacing therapy and standard medical care went on to seek CBT or graded exercise therapy.

Perhaps and suppositions have nothing to do with science.
And data shows those who underwent CBT and GET after didn't get better.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
Interesting open access piece from Lancet Psychiatry


Amongst other things it highlights the problems of:
  • Unblinded treatment groups
  • Like of appropriate controls
  • Relying on subjective outcomes

A bit limp maybe? It seems to be saying, 'oh dear, how tricky it is to do trials - ah well'. No suggestion of how valid trials might actually be designed.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
But acknowledging such big generic problems is surely progress.


MM, not sure. Everybody knows the problems. The question is do you carry on saying 'ah well this is the best we can do in psychiatry' or do you say 'we need to address this'. My worry is that the punch line is the old chestnut that even if you have trials you need to see how it really works in the clinic. I.e. the trials aren't really that important anyway, we can see if things work just by getting experience in the clinic. That is a retrograde position - if it is really meant like that.

What the journal should have had was a cutting edge analysis of what can be done to rescue useful results from all the problems - something like a resume of a good PR discussion thread.
 

A.B.

Senior Member
Messages
3,780
If one has no biomarkers to work with, then one needs to look at real world outcomes that are probably not influenced much by reporting bias: employment status, receipt of disability, measured activity levels, hospitalization, etc.

I suspect doing so would be an eye opener. PACE is probably not the only case of ineffective treatment being made to look effective by intentionally working with outcomes prone to bias.
 

user9876

Senior Member
Messages
4,556
If one has no biomarkers to work with, then one needs to look at real world outcomes that are probably not influenced much by reporting bias: employment status, receipt of disability, measured activity levels, hospitalization, etc.

I suspect doing so would be an eye opener. PACE is probably not the only case of ineffective treatment being made to look effective by intentionally working with outcomes prone to bias.
I do wonder if having various consumer wearables such as fitbits and watches that can monitor various activity levels, heart rates etc could make long term monitoring of activity much easier than in the past. It doesn't need to be that accurate either as for good treatments we should be looking for major changes.