PACE trial TSC and TMG minutes released

[Daisymay]

I am not sure whether or not it would be usual to have such a large number of 'independent' people. For a multi centre trial I suspect it would be usual to have some sort of oversight committee. I think this would be standard if MRC and/or NIHR were involved and probably all funding bodies would be represented.

I suspect various people may have moved on by the tie the trial started. I think Paul Dieppe had moved on and Aylward had left DWP.

Thanks, would it be normal to have an Analysis Strategy Group? And if so why wouldn't they not have been mentioned earlier in say in the protocol?

I wonder when they came into existence, at the beginning or when they realised they needed to work out how on earth they could come up with seemingly positive results?

 

[Trish]

Thanks, would it be normal to have an Analysis Strategy Group? And if so why wouldn't they not have been mentioned earlier in say in the protocol?

In my simplistic ignorant mind, planning the analysis would have all been done at the same time as writing a detailed protocol and before getting ethical and funding approvals and starting to recruit patients.

They had to do some dummy calculations anyway to work out what sample sizes they needed in order to get robust results.

Surely the thing to do at that stage would be to plan what analysis would be appropriate to test whether their primary and secondary outcome measures were significant, and what boundaries they would set for each measure and a combined measure to represent clinically significant improvement, recovery and cost effectiveness.

They could have computer simulated the whole thing and had the statistical analysis plan ready to run as soon as the real data was unblinded and collated.

Well, that's what I'd do anyway, but what do I know.

 

[JohnTheJack]

Horton described the PACE paper as 'eagerly awaited'.
Was he short of good copy?
Considering that the great majority of physicians have still to this day never heard of the PACE trial - all about some physio or counselling for chronic fatigue or something? - why on earth would he think it newsworthy?

I'd always thought that his vigorous support for the trial had come after its publication, once the journal was invested in the paper. It seems he was onboard from much earlier.

It is strange. I think it goes back to the PR the BPS crowd had been running. They clearly had already convinced many, including Horton, that PACE was a slam-dunk and going to prove right what they had been saying for years.

 

[JohnTheJack]

Apologies in advance for the length of this post, and for any difficulties that the formatting causes people. I've struggled to work out how best to lay it all out to make it easy to follow, but I accept I've probably failed miserably.

Yes, that's how it seemed to me. Good post, thanks.

 

[JohnTheJack]

So they talk of the Analysis Strategy group.

From the PACE paper, my bold:

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60096-2/fulltext

PACE trial group

Trial Steering Committee (independent members)—Janet Darbyshire (Chair), Jenny Butler, Patrick Doherty, Stella Law, M Llewelyn, and Tom Sensky. Observers—Sir Mansel Aylward (Department for Work and Pensions, London, UK), Sir Peter Spencer and Chris Clark (Action for ME, Bristol, UK), Stephen Stansfeld (Queen Mary University of London, London, UK), Alison Wearden (Fatigue Intervention by Nurses Evaluation trial), and members of analysis strategy group and writing and publication oversight committee. Data Monitoring and Ethics Committee—Paul Dieppe (initial Chair), Astrid Fletcher (final Chair), and Charlotte Feinmann. Independent assessors of the trial safety data—Hiroko Akagi, Alastair Miller, and Gavin Spickett. Independent assessors of therapy—Barbara Bowman and Deborah Fleetwood.

So no names are given in the PACE paper of who was involved with these groups, just a mention of their existence.

Do we have any idea from an other sources who were in the Analysis and Strategy Group or the Writing and Publication Oversight Committees?

Jonathan, is this normal practice to have such committees for a research trial?

The ASG is named:
The analysis strategy group, chaired by MS, consisted of HLB, TC, JCD, KAG, ALJ, LP, PDW, and RW. The statistical analysis plan was written by the analysis strategy group and approved by the trial steering committee and data monitoring and ethics committee before the analysis was started.

 

[Adrian]

In my simplistic ignorant mind, planning the analysis would have all been done at the same time as writing a detailed protocol and before getting ethical and funding approvals and starting to recruit patients.

They had to do some dummy calculations anyway to work out what sample sizes they needed in order to get robust results.

Surely the thing to do at that stage would be to plan what analysis would be appropriate to test whether their primary and secondary outcome measures were significant, and what boundaries they would set for each measure and a combined measure to represent clinically significant improvement, recovery and cost effectiveness.

They could have computer simulated the whole thing and had the statistical analysis plan ready to run as soon as the real data was unblinded and collated.

Well, that's what I'd do anyway, but what do I know.

I agree, I think things should move to the analysis being pre-coded so that as the last data is added to the database then the results tables would be produced.

The PACE people seemed to have trouble 'cleaning data' so applying certain checks on the data can be helpful to detect possible errors.

 

[Adrian]

When they were looking to raise the SF36 score acceptable for recruitment the PACE PI's understood just how subjective the questionnaires were. (Just not when used for results)

The PIs noted that the TSC had originally reduced the SF-36 cut off score from 70 to 60 in order to ensure that more disabled patients were entered into the trial. Centres’ experiences of running the trial so far are that the SF-36 is measuring subjective and not objective disability so this original concern was not now considered to be an issue. The SF-36 is a self report measure and patients’ perception of their physical function is assessed with this scale. There have been many incidents of patients objectively appearing as very disabled (using wheelchairs or mobility cars) scoring as too well on the SF-36 and thus being excluded from the trial. By contrast, many objectively fit and able patients who are still able to work and run the family home are presenting with low scores on the SF-36 and entering the trial.

 

[Sly Saint]

Sorry if this is not the right place to put this but it was posted at the other place and thought it was relevant.
SW always insists he had 'nothing to do with the PACE trial'

 

[Lucibee]

Keith noted this from meeting 16:

Step test - a participant at Edinburgh reported an AE as a result of the step test. Reported physical set back from doing the test and emotional set back at not feeling they had done very well. In conclusion the participant acknowledged that they had pushed themselves too hard (possibly in response to wanting to do well for the RN).

Discussion held regarding instructions to the step test to try to avoid a repeat of this in the future.

My question would be: Is there a safe way to do the step test in people with ME/CFS, given that it exercises to exhaustion? It's probably a reasonable objective measure because it doesn't allow the subject to pace themselves.

I'm presuming the step test they used is similar to this: https://en.wikipedia.org/wiki/Harvard_step_test

 

[Jonathan Edwards]

Thanks, would it be normal to have an Analysis Strategy Group? And if so why wouldn't they not have been mentioned earlier in say in the protocol?

No, I agree with Trish that it is very odd for there to be an Analysis Strategy Group in existence after the trial has formally commenced. By 2000 it was very clear to people running trials that your analysis needed to be decided before you started. It rather looks as if the MRC fell well below basic standards on this in its 'CTU'.

More and more the message from this trial is not so much that the authors were incompetent but that the MRC was incompetent in its role as a guiding influence.

 

[Jonathan Edwards]

I'd always thought that his vigorous support for the trial had come after its publication, once the journal was invested in the paper. It seems he was onboard from much earlier.

It is strange. I think it goes back to the PR the BPS crowd had been running. They clearly had already convinced many, including Horton, that PACE was a slam-dunk and going to prove right what they had been saying for years.

In the radio recording that someone uploaded here a while back Horton says the trial was eagerly awaited. It was clear from his tone that he knew well in advance that he was expecting a slam dunk trial.

I think this has to confirm the suspicion one has always had that the editorial policy at the Lancet was little more than mingling with the in-crowd and picking up what was a hot favourite. Again, in this regard the Lancet falls way below peer review standards in regular specialist journals like Arthritis and Rheumatism or indeed New England Journal of Medicine. One always suspected that but one did not often have the chance to see it in action.

 

[Daisymay]

Sorry if this is not the right place to put this but it was posted at the other place and thought it was relevant.
SW always insists he had 'nothing to do with the PACE trial'
View attachment 2329

So from TMG meeting 4, 23rd January 2004:

"7. Trial Steering Committee (TSC): Final Membership and Date of 1st Meeting

The MRC have confirmed approval of the membership. REDACTED, who is the director of the Clinical Trials Unit at the MRC, has agreed to chair the TSC. REDACTED has vast experience of clinical trials.... "

Does that therefore mean that REDACTED here is Wessely?

Does he really have "vast experience of clinical trials" ??

 

[Indigophoton]

In the radio recording that someone uploaded here a while back Horton says the trial was eagerly awaited. It was clear from his tone that he knew well in advance that he was expecting a slam dunk trial.

Not just Horton. The DWP provided some of the funding on the expectation that the trial would show CBT and GET to be successful. When asked why they funded PACE, they replied,

We believe that the findings of the trial will contribute to the continuingly growing evidence base, which informs the development of health and work related policy, policy based on the large body of evidence showing that work is good for physical and mental wellbeing and that being out of work can lead to poor health and other negative outcomes.

https://www.whatdotheyknow.com/request/part_funding_of_the_pace_trial_b

 

[Lucibee]

Does that therefore mean that REDACTED here is Wessely?

No. Janet Darbyshire was Director of the MRC CTU in 2004, I think. Wessely's CTU was at Kings.

 

[Jonathan Edwards]

No. Janet Darbyshire was Director of the MRC CTU in 2004, I think. Wessely's CTU was at Kings.

There are sentences on the net looking very like the one @Daisymay quoted where the name is Wessely. He was certainly director of the CTU responsible for PACE as far as I can see, at least at some point. What is not clear to me is whether this is the entire MRC CTU or whether it is a subsection.

 

[Jonathan Edwards]

Not just Horton. The DWP provided some of the funding on the expectation that the trial would show CBT and GET to be successful. When asked why they funded PACE, they replied,

https://www.whatdotheyknow.com/request/part_funding_of_the_pace_trial_b

Yes, I think the role of DWP is fairly well documented. The question is where Horton comes in if he is supposed to be an independent editor publishing purely on scientific merit. Why was he eagerly awaiting such a scientifically boring trial?

 

[Lucibee]

I think this has to confirm the suspicion one has always had that the editorial policy at the Lancet was little more than mingling with the in-crowd and picking up what was a hot favourite.

*cough* I think it says more about the expectation that the more prestigious the institution and affiliations (and numbers of gongs on the byline), the more robust the research will be. I think The Lancet takes it way too much on trust that things will be done properly under those circumstances.

"It was a very easy trial to publish" because they felt they didn't need to do any checks. In my view, the more profs on the byline, the more scrutiny they should employ, since all the annoying pedantic juniors like me won't have been involved! It's airline safety protocols all over again.

 

[Jonathan Edwards]

I think it says more about the expectation that the more prestigious the institution and affiliations (and numbers of gongs on the byline), the more robust the research will be. I think The Lancet takes it way too much on trust that things will be done properly under those circumstances.

That is the more charitable reading. I don't actually think it has to do with institutional prestige and affiliations. How did Andrew Wakefield get to be published? The Royal Free surgery department was hardly high profile. Horton did not come sniffing around when I was about to publish in NEJM from perhaps the most prestigious clinical science faculty in the world at the time - I guess because I did not go around touting my wares to chummy editors.

 

[Barry]

Yes, I think the role of DWP is fairly well documented. The question is where Horton comes in if he is supposed to be an independent editor publishing purely on scientific merit. Why was he eagerly awaiting such a scientifically boring trial?

You typically eagerly await something when you are already primed up for it being likely to be what you want it to be. Primed how and by who?

 

[Jonathan Edwards]

You typically eagerly await something when you are already primed up for it being likely to be what you want it to be. Primed how and by who?

Well, somebody here ought to know. People here seem to know everything! Or they soon enough find out.

I can think of some candidates.