Syndrome de fatigue chronique : Que conclure de la réévaluation de l’essai clinique PACE ?

https://actualite.housseniawriting....a-reevaluation-de-lessai-clinique-pace/26233/

Peut-être y a-t-il quelqu'un qui parle couramment le français et qui peut en faire l'écriture. J'ai déjà eu un bon niveau de français, mais il est fatigant pour moi de lire de longs articles.

 

Of course there is always Google Translate:
https://translate.google.com/transl...tion-de-lessai-clinique-pace/26233/&sandbox=1

 

I'm giving it a go, despite being stupid-tired. Chunking it down to several posts.


Chronic Fatigue Syndrome: What Can we conclude from the reevaluation of the PACE Trial?

Publié par : Jacqueline Charpentier Publication : 23 mars 2018Heure : 2:00 dans Syndrome de fatigue chronique Laisser un commentaire

The PACE cliunical trial on CFS is making news again. Researchers have reevaluated the first paper and the results show that the authors exaggerated the results but cannot be qualified as fraudulent.

CFS and the clinical trial PACE have caused a lot of ink to flow. Published in 2011, the trial showed that the therapies GET and CBT were effective in treating CFS.

GET pertains to graded exercise therapy, and TCC is cognitive behavioural therapy.. If the results were shown to be positive, the patients were of a different opinion in claiming that there were not improvements, and sometimes, their symptoms were worsened.



CFS and the controversy of a clinical trial

The clinical trial was financed by british taxpayers; certain patients requested access to the trial data and the authors refused for various reasons. A legal action was required to force the university to reveal the data. The patients utilised the data to offer different interpretations of the results, but the common point was that the authors of the clinical trial had exaggerated the results.

One of the most high-profile critical articles came from David Tuller of UC Berkeley of California that highlighted numerous methodological errors of the trial, notably the absence of a rigourous randomised control.

Some claim that the criticisms are ill-informed. They would refuse GET because they dont wish to do exercise therapy or CBT, because of their fear of secondary psychological effects. [?!]

 

The different camps are divided with the patients calling fraud, while one part of the scientific community finds the trial simply limited.

This is why a reevaluation of the Pace trial, published in BMC Psychology, was especially anticipated, but the result will not please either camp.

The Results of the new analysis of the PACE Trial

The paper indicates that the assertions regarding the effectiveness of GET and CBT in the PACE trial were perhaps exaggerated.

The authors reanalysed the data from the PACE trial by following the trial plan presented in the original protocol. They did it in a transparent manner and made reasonable hypotheses concerning the missing information.

The results of this reanalysis raise uncertainty regarding the original analysis of the PACE tiral, because it exposes the fact that the results are sensitive to how the primary outcome measure is defined.
It would be inappropriate to use these new results to confirm the ecffectiveness of CBT and GET or to classify them as ineffective because an improvement was observed by certain measures, but not by others, the estimates are imprecise and the reasons for the change in protocol are not clear.

When planning a randomized trial, it is recommended to have a carefully planned protocol and analysis plan that is published in advance on a trial registry and/or research journal. One of the objectives of trial registries is to avoid selective reporting of test results that can lead to exaggerated or false claims about the effectiveness of treatments. However, it should be noted that the PACE trial was planned at a time when trial registration was still in its infancy and selective reporting problems were less well known. Differences between protocol and analysis were and are still common and initial analyzes should not be invalid if the changes were well justified and planned before data analysis.

Reanalyses of trial data such as this are rare. However, as journals apply data sharing rules, analyzes will increasingly be exposed to external scrutiny in this way.

 

What do the data show?
The authors appear to have attentively followed the original PACE protocol and presented their own analyses in a reasonably clear and transparent way. Sensible assumptions were made about the missing data and the data was analyzed in different ways to show that the results are robust. This reanalysis shows that if the authors of the initial study had followed their own protocol, they would have reached very different conclusions. The authors of this paper make appropriate use of their findings to raise concerns about the robustness of previously formulated claims on the efficacy of CBT and GET based on the PACE trial.

Additional unplanned analyses were performed on long-term data collected at least 2 years after treatment. These analyses were repeated after exclusion of patients who received additional treatment after the trial, suggesting that conclusions about the absence of long-term effects are reasonably robust and not the result of post-test interventions.

The Limits of this new analysis

There are points in the original PACE protocol that were either inconsistent or open to interpretation. The authors of this new paper seem to have chosen the most extreme analysis to put forward their point of view. For example by making adjustments for 6 comparisons where 3 or 5 comparisons are also described, and by focusing only on 52 week data.

The authors rely heavily on p-values and statistical significance thresholds when presenting results. This is a rather outdated approach and there is a lack of information on the extent and precision of treatment effects in most cases. The authors made few attempts to uncover the reasons for the protocol discrepancies in the PACE trial or the point where they were made. The evaluators could have been invited to comment.

No adjustment was made to the reanalysis of the patient's characteristics even if this had been planned in the initial trial. Sufficient data to do this were not available. The inclusion of appropriate demographic variables could improve the accuracy of the results.

Only 52-week data were analyzed yet data were collected at 12, 24 and 52 weeks. An analysis taking into account measurements over time could have led to more accurate results.

The new paper may give the impression that all or almost all of the evidence on CBT and GET comes from the PACE study, as this paper suggests that it seems unlikely that new research based on these treatments will yield more favorable results. In fact, CBT and exercise therapies have been studied in several other studies that have been reviewed in Cochrane reviews. The latest Cochrane Review includes 8 studies other than PACE and offers positive conclusions about some aspects of the effectiveness of exercise therapy.

Experts' opinion on this reevaluation

For Chris Ponting, professor of medical bioinformatics at the University of Edinburgh, the new analysis shows that the clinical trial does not reach a meaningful statistical result.

In 2011, the PACE group interpreted their randomized trial data as meaning that Cognitive Behavioral Therapy (CBT) and Graduated Therapy (GET) can be safely added to specialized medical care to moderately improve the outcomes of CFS.

Since then, Wilshire and her coauthors render a new analysis of PACE trial data. This reanalysis was necessary in part because the research group had revised its analysis from the plan published in its protocol. This revision meant that, in theory, some trial participants could be considered patients, but they were considered to be cured at the end of the trial even if their symptoms did not improve, or even worsened. Wilshire et al. provide proof 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 originally 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 for these modest effects. Specifically, they argue that they are simply explained by the high expectations of participants in CBT and GET that their treatments would be effective (ie, a placebo effect). Expectations are exacerbated, they say, when participants are not blinded by their treatment and are assured that their treatment is effective as was the case for the PACE trial. The lack of significant gains in objective outcome measures, such as fitness, indicates that gains on self-report measures may not be reliable. This could largely explain the modest effects observed after one year and the disappearance of these effects thereafter. The authors also assert that the lack of substantial and long-lasting effects of CBT and GET observed from a trial the size of PACE implies that these therapies are unlikely to be widely effective.

So, according to Ponting, the results have little statistical significance as the moderate positive effect could be compared to placebo, even after a year.

 

So, Scientific fraud or not?

The whole question is whether the authors of the PACE trial are guilty of scientific fraud deserving a retraction of their study. If a salesman gives you a seed promising you that it will become an apple tree that will reliably give 20 apples and you follow the process but you only have 10 apples, has the seller lied? Yes, but is his process false, no.

And that's the whole problem of this PACE clinical trial. It is not mediocre enough to deserve a retraction, but it is bad enough to systematically discourage two therapies as is the case today. This is a bad study, but the worst is that after the publication of their essay, the authors held a press conference where they stated that twice as many patients who participated in GET and CBT, were able to return to a normal state.

To say that it is exaggerated is euphemism. Moreover, in an open letter signed by 42 scientists who criticized the clinical trial, there is also the conflict of interest of the authors that was not published. Thus, several researchers who participated in this clinical trial had financial interests as consultants for disability insurance companies. Several researchers who participated in this clinical trial had financial ties as consultants for disability insurance companies. Their consultations indicated to the insurance companies that their clients could follow the two recommended therapies to regain employment. Hype and hidden conflicts of interest, this is troubling.

But the media also have their share of responsibility, because the terrible misfortune which accompanies chronic fatigue syndrome is that it was first considered a psychiatric rather than a physiological disease. So in 2015, The Daily Telegraph ran the headline that a study shows that CFS patients can improve their health with exercise and "positive thoughts".

The debate is far from over with the knowledge that in the summer of 2017, the CDC quietly removed the recommendations for CBT and GET for CFS under the pressure of activists, according to part of the medical community. If the other studies, which are not [musty?] show positive effects of these therapies, the question remains about the scope of these positive effects and whether they should be systematically recommended to patients.


~Apologies in advance for mistakes, omissions, etc, exhausted so am off to sleep~

 

Before I sleep: @Hutan, @Tom Kindlon

If this is viewed as copyright violation, please copy the (probably braindead) translation so Tom can have it, and delete my posts.
Or leave it for a day or two so people can see it before axing it.
I really must go sleep now.

 

Yes, there is work to do. I have already been through the exercise trials in the Cochrane review and they are all mouldy. I am now going through the CBT trials and they are mouldy so far. But Cochrane is showing little sign of shifting its stance in response to criticism.

The next task is a much bigger one, although not necessarily a more difficult one now. It has to be made clear that for ME/CFS the MRC, Cochrane and the Lancet - the key guardians of quality control - have all been incompetent. I am working on this but it may take me some time.

The message is simple. None of these trials provides reliable information. What is remarkable is how consistently patients say what they have been primed to say, no matter what sort of therapist tells them to. However, getting the simple message across in a way that has impact will require work.

 

Moldy actually seems to be quite a good word there.

 

Also, thanks for your work, @Allele . I can’t read French so I appreciate your efforts to get it in more readable English.

 

Hi @Trish
It's not a recognised News source. It's a blog run by a few people (unclear how many) and interested in science. A cursory look shows that they receive small donations via Patreon and also accept sponsorships and sponsored articles for the blog. They are based in Madagascar.

 

A lot of this article is based on the Science Media Centre material on the paper.

 

I think people who are sceptical about claims that CBT and GET are effective treatments will be more pleased by the BMC Psychology paper than those who are proponents of these therapies.

The preceding sentence does refer to fraud and our paper doesn't comment on this.

 

As there is probably not much material on the paper in French, I decided to tweet this article:

https://twitter.com/user/status/976956898909065219

https://twitter.com/user/status/977653268938665985

 

Oh, I'm glad you highlighted that bit, I've corrected my typo back to BMC.
And I agree with you about who will be pleased. Was unsure why the author said that. The article has bits from the SMC spin too and was an odd amalgamation of PoVs. Overall good though, I thought. Very glad your paper is getting international attention.

 

I couldn’t work out why they were saying “fraud”, either. In the Google translate version, that part links to this:
https://translate.google.com/translate?hl=en&sl=fr&tl=en&u=https://actualite.housseniawriting.com/sante/syndrome-fatigue-chronique/2018/03/23/syndrome-de-fatigue-chronique-que-conclure-de-la-reevaluation-de-lessai-clinique-pace/26233/&sandbox=1

Which says it’s a translation to French of an article by Steven Lubet. He was pretty critical, but I couldn’t see that word in the translation and I don’t recall it being used in any public-facing contexts that I saw until, if I recall correctly, the last month or so.