PACE Trial and PACE Trial Protocol

[biophile]

White starts out with stating that "not many clinicians or scientists would argue with the campaign by AllTrials to register and report the full methods and results of clinical trials". Yet his own actions with the PACE Trial strongly indicate that he is one of those clinicians or scientists who would argue with the AllTrials campaign! He has been painfully slow in reporting the full methods and results of his own infamous trial and resists all attempts at releasing requested data, including that which was promised in the original registered protocol.

White then argues that full public disclosure of trial data is bad because the "anonymised" data is not adequately anonymous. I am not sure to what extent the BMJ are proposing that all data should be released, but somehow I doubt that the people behind AllTrials are insensitive to issues relating to patient confidentiality.

God forbid that somebody applies some common sense, let alone expertise, to this problem.

Of course, there have been lots of other freedom of information requests which would not break confidentiality e.g. the data for the original primary outcome measures, deterioration rates, recovery rates (as in original protocol), etc. and he has released virtually nothing following such requests.

Precisely, and then there is this:

http://www.alltrials.net/wp-content/uploads/2013/01/Missing-trials-briefing-note.pdf

Journals can commit to a similar policy undertaken by the BMJ, whereby ‘trials of drugs and medical devices will be considered for publication only if the authors commit to making the relevant anonymised patient level data available on reasonable request.’

I am reminded of this recent editorial by Tracey Brown hosted on thecochranelibrary.com (April 2013):

http://www.thecochranelibrary.com/d...me-for-AllTrials-registered-and-reported.html

One of the reasons that the problem of missing trials has not been addressed is that discussions have taken place behind closed doors, amid promises that "it is being fixed". Behind those closed doors, arguments to slow and complicate the path to improvement can thrive. These arguments have been redeployed against the AllTrials initiative. The problem is fixed. It shouldn't be discussed in public because it undermines trust in medicine. Publishing research results causes scare stories. The regulator has what it needs, and we should be content with that. Patients are alarmed that their information might be shared. It wastes resources. The problem is being exaggerated. And so on.

These are not, though, the arguments of people with greater insight into the problems of clinical trial reporting. They are the arguments of people who don't want change. The problem is not fixed. We have seen a slow improvement in registration compliance and reporting rates, but the medicines that are currently prescribed for patients already have marketing authorisation. This is why AllTrials is calling for retrospective publication of trials relating to treatments in current use. Talking only about the conduct of future trials is just kicking the ball further up the street, which is what has happened since Iain Chalmers first sounded the alert on the problem of non-reporting 20 years ago.[3] Registering protocols and reporting outcomes do not present insurmountable patient confidentiality issues. GlaxoSmithKline, the first pharmaceutical company to sign up to AllTrials, has agreed to publish the results of all trials going back to its formation as a company, which shows it can be done. Under the glare of the public spotlight now on this issue, the arguments against communicating trial results disappear into the shadows.

3. Chalmers I. Underreporting research is scientific misconduct. JAMA 1990;263(10):1405-1408. dx.doi.org/10.1001/jama.1990.03440100121018

White is still being part of the problem, I doubt he will be contributing much to the solution.

Another point to consider:

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-‐analysis of individual patient data for 10 801 women in 17 randomised trials. The Lancet. 2011 Nov;378(9804):1707–16. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61629-2/abstract

Analyses such as this present challenges in ensuring confidentiality for individual patients (although these can be overcome, and the work of the YODA data sharing project at Yale presents one interesting early proposal of how to manage these issues). This is a different issue, however, to claiming confidentiality about the existence and results of the trials themselves, and withholding information about their conduct.

http://www.alltrials.net/wp-content/uploads/2013/01/Missing-trials-briefing-note.pdf

All efforts at attaining additional information about how the PACE Trial was conducted has been fiercely resisted, especially the minutes to the meeting about why they changed the protocol etc. Perhaps there would be little or no need to request such information if they actually published the statistical analysis plan?

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.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065633/

This statistical analysis plan was supposedly finalized before the analysis was started. The trial ended in January 2010 and the Lancet paper was submitted for fast track publication around January 2011. So it probably has existed for about 3 years but has still not seen the light of day, despite promises made 28 months ago (and IIRC several months ago too when it was stated that something was being prepared for publication or possibly even in the peer-review phase?).

Unless of course, it is what a recent blog opined was a "work in progress":

"One final observation. QM nearly got itself into trouble in this case because of its curious publication strategy. It is odd to publish research about the merits of a given set of treatments, without having finalised one’s analytical work on the therapy-specific demerits. From a medical ethics perspective, I wonder to what extent the clinicians and patients appreciated that to some extent the 2011 Lancet publication was work-in-progress – because that is the implication of QM’s arguments on this appeal."

http://ukhumanrightsblog.com/2013/0...-from-a-randomised-controlled-trial-on-mecfs/

What is the point of PACE publishing a protocol when much of it was changed anyway. Similarly, why did they even bother registering at http://www.controlled-trials.com/ISRCTN54285094 ?

PDW has received several Freedom of Information requests from members of the public for all the data from a recent trial of non-pharmacological treatments of chronic fatigue syndrome.

http://dx.doi.org/10.1136/bmj.f3379

I wonder how many FOI requests in total? FWIW, knowing that the results of a trial would be publicly available with adequate anonymity, would indeed encourage me and probably many others to participate in it.

 

[biophile]

I could not help repeating this post from another thread:

Image credit:

‘Keeping the Bastards Honest’ – The Promise and Practice of Freedom of Information Legislation
This thesis is presented for the degree of Doctor of Philosophy of Murdoch University in 2006
Johan Lidberg, MA Journalism
http://www.smh.com.au/reports/johanlidberg.doc

PS - "Keeping the Bastards Honest" is a common political phrase in Australia, not meant to be a personal attack.

 

[Dolphin]

If anyone has the time, one could reply to PDW's letter, either here: http://www.bmj.com/content/346/bmj.f2961 (under the original article where his rapid response is) or here, http://www.bmj.com/content/346/bmj.f3379 , the link for the printed version of the letter.

 

[Firestormm]

Interesting that AllTrials has been endorsed by the Royal College of Psychiatrists. I think White was just raising a concern. But that it's a non-concern really. All data should be made available although in doing so it will increase downstream costs - I mean presumably this latest release from PACE will need to be paid for from somewhere and it seems it wasn't planned. If in future all data from Trials is made available - the companies/organisations producing the Trials will see an increase in costs - and that will be passed on in some way. Am not sure how costings are built into a model to account for 'follow-up' investigations as a result of enquiries - they must be in some way - but it's all an additional burden and could delay drug availability. I support the AllTrials initiative of course but worth thinking about it's impact.

 

[user9876]

No they're not, which is why government statistics departments who request datasets from other departments specify which variables they need for their analysis. Any that they don't need, or can't adequately justify needing, are stripped out. Such data requests are considered on a case-by-case basis by someone whose job it is to analyse at what level of aggregation of variables confidentiality might be breached.

God forbid that somebody applies some common sense, let alone expertise, to this problem. Just take locality out, for a start. Who wants that?

This disgusts me.

There has been a lot of work on privacy and what can be inferred however I expect White is unaware of this. The real problem comes with diseases that are very rare hence a trial is covering a large % of people.

There are tricks to play with the accuracy of information such as location. You don't need to give a post code just a city or region or leave it out as its not useful (depending on the problem). I've seen others play statistical tricks when sharing commercial data bases so for example they will change the ages with a known error distribution so that the overall statistical properties don't change (however might be bad for subtype analysis).

 

[user9876]

Interesting that AllTrials has been endorsed by the Royal College of Psychiatrists. I think White was just raising a concern. But that it's a non-concern really. All data should be made available although in doing so it will increase downstream costs - I mean presumably this latest release from PACE will need to be paid for from somewhere and it seems it wasn't planned. If in future all data from Trials is made available - the companies/organisations producing the Trials will see an increase in costs - and that will be passed on in some way. Am not sure how costings are built into a model to account for 'follow-up' investigations as a result of enquiries - they must be in some way - but it's all an additional burden and could delay drug availability. I support the AllTrials initiative of course but worth thinking about it's impact.

There is a national data archive http://data-archive.ac.uk/ which is easily accessable to academics and private researchers can apply for access as well. It includes various health survey data and could also start holding MRC trial data. They have two ideas of data release. One where you can download the data set and a second one for more sensitive data where they give you access to statistical tools with the data loaded but you never get a copy of the data.

 

[Dolphin]

An example of why it's important to ideally getting points on the PACE Trial published:

Restoring Invisible and Abandoned Trials: A Creative Approach to a Public Good; Now a Creative Approach to Implementation is Needed
By Margaret Winker and Virginia Barbour
Posted: June 13, 2013

[..]


For misreported trials—Evidence of misreporting (ideally, published letters or other articles in the scientific literature or documentation of communication with the original trial publication author(s) detailing the misreporting) and a failure to correct the scientific record.

http://blogs.plos.org/speakingofmed...reative-approach-to-implementation-is-needed/

 

[Esther12]

Interesting that AllTrials has been endorsed by the Royal College of Psychiatrists. I think White was just raising a concern. But that it's a non-concern really. All data should be made available although in doing so it will increase downstream costs - I mean presumably this latest release from PACE will need to be paid for from somewhere and it seems it wasn't planned. If in future all data from Trials is made available - the companies/organisations producing the Trials will see an increase in costs - and that will be passed on in some way. Am not sure how costings are built into a model to account for 'follow-up' investigations as a result of enquiries - they must be in some way - but it's all an additional burden and could delay drug availability. I support the AllTrials initiative of course but worth thinking about it's impact.

Are you talking about the harms data? I think that they're acting like they were always planning to release this (and that could even be true).

For academics, making data available should just be part of the job description, rather than an onerous extra cost that needs to be accounted for. It's what they're there for!

An example of why it's important to ideally getting points on the PACE Trial published:

http://blogs.plos.org/speakingofmed...reative-approach-to-implementation-is-needed/

I wonder how that will affect attempts to get PACE data available. It has been quite amusing watching the alltrials campaign occurring at the some time as CFS patients trying to get access to PACE's protocol defined outcomes as militant harassers. It has helped remind me how driven by prejudices many influential people in our society still are.

 

[Bob]

I've just noticed that Action for ME's current pacing booklet refers to the PACE Trial a number of times.
The booklet also mentions CBT & GET quite a lot.
See pages 11, 12 & 13 for the bits about the PACE trial:
http://www.actionforme.org.uk/Resources/Action for ME/Documents/get-informed/pacing-booklet.pdf

I've come to the conclusion that Action for ME don't have a grasp of the PACE trial results, as demonstrated by the following extract from the booklet:
"adaptive pacing as defined and applied in the PACE trial has now been proven to be safe for all and effective for at least one in three people"

For myself, pacing is essential, and exceptionally helpful, but the PACE trial did not demonstrate that it is effective for "at least one in three people".


Action for ME's medical adviser, Dr Alastair Miller has put out more than one misleading statements, about the PACE trial, on the SMC's website (my emphasis):

"This trial represents the highest grade of clinical evidence – a large randomized clinical trial, carefully designed, rigorously conducted and scrupulously analysed and reported. It provides convincing evidence that GET and CBT are safe and effective and should be widely available for our patients with CFS/ME."
http://www.sciencemediacentre.org/e...-treatments-for-chronic-fatigue-syndromeme-2/

“This is another encouraging result to come out of the “PACE stable” showing that recovery from CFS/ME is not only possible but considerably more likely with the current therapeutic approaches of cognitive behavioural therapy and graded exercise therapy."
http://www.sciencemediacentre.org/e...nto-therapies-for-chronic-fatigue-syndromeme/

This shows a disturbing level of either ignorance or bias, for a medical adviser of a large patient support group.
Telling patients that CBT and GET were found to be 'effective' (when they were not) and led to a 'recovery' (when we don't know if any patients actually recovered, in lay terms), is misleading and unhelpful.

 

[Esther12]

I think that it's more cynicism that stupidity. Action for ME seem to just want more money for CFS stuff... I don't think that they even consider whether this could be unhelpful. More money = more prestige, and a number that they can point to that goes up.

 

[biophile]

Good find Bob. I am not sure where they came up with the claim that "adaptive pacing as defined and applied in the PACE trial has now been proven to be safe for all and effective for at least one in three people". That statement came after a discussion of PACE and patient surveys, so who knows. One figure which comes in mind is that 31% of the APT group did report a "positive change" on the CGI in the PACE Trial.

Earlier it states that "While the trial found all four approaches to be moderately effective, it found this particular form of pacing (adaptive pacing) to be less effective than CBT and GET at improving function." Here it would appear they are taking all the APT improvements from baseline as granted, not accounting for the SMC improvements.

The booklet repeatedly discusses GET etc as forms of pacing, even calling GET "pacing up", and points out that "pacing in one form or another remains one of the key approaches used by therapists in specialist NHS M.E./CFS clinics" because "a limited form of pacing (setting baseline) is the starting point for graded exercise therapy". Therefore it is possible that the figure "at least one in three people" is actually the GET figure!

 

[ukxmrv]

AFME has always supported the PACE trial. Their old CEO Chris Clark was on one of the original committees.

"PROPOSED MEMBERSHIP OF THE TSC

The membership of the existing TSC was agreed but it was also suggested that it would be worth inviting additional members. It was suggest that Chris Clark, CEO of Action for ME should be invited as observer, and that we should also invite an independent physiotherapist and occupational therapist to ensure that these views were represented on the committee. It was suggested that these individuals ought to be from outwith the field of CFS/ME and have experience in a complementary area such as cardiac rehabilitation or chronic pain. Endorsement of their membership by the appropriate professional bodies was desirable but we would not require that they would be regarded as representative.

Action: PW to invite Chris Clark, as an observer.

Action: PW to suggest names of a physiotherapist and occupational therapist for approval by the TSC Chair."

Their other old CEO Sir Peter Spencer co-authored a letter to the BMJ with Peter White.

One of their Trustees, Stephen Halpern, was a Patient Rep at Barts.

They have been pushing CBT and GET (in all it's various guises) for years. Completely in bed with this crowd.

 

[Esther12]

An example of why it's important to ideally getting points on the PACE Trial published:



http://blogs.plos.org/speakingofmed...reative-approach-to-implementation-is-needed/

Having looked again at this, I think that these campaigns make it very difficult for white et all. to argue against foi s asking for the outcomes laid out to n pace's protocol.

 

[Bob]

Good find Bob. I am not sure where they came up with the claim that "adaptive pacing as defined and applied in the PACE trial has now been proven to be safe for all and effective for at least one in three people". That statement came after a discussion of PACE and patient surveys, so who knows. One figure which comes in mind is that 31% of the APT group did report a "positive change" on the CGI in the PACE Trial.

I reckon you're probably right about the CGI scores, but even that is an absolute percentage, and not relative to the SMC group. It's all a bit random.

Earlier it states that "While the trial found all four approaches to be moderately effective, it found this particular form of pacing (adaptive pacing) to be less effective than CBT and GET at improving function." Here it would appear they are taking all the APT improvements from baseline as granted, not accounting for the SMC improvements.

I think they just haven't got a clue about it at all. It all seems just totally random, doesn't it. It does perhaps suggest that their medical advisor is fairly ignorant, and totally out of his depth.

The booklet repeatedly discusses GET etc as forms of pacing, even calling GET "pacing up", and points out that "pacing in one form or another remains one of the key approaches used by therapists in specialist NHS M.E./CFS clinics" because "a limited form of pacing (setting baseline) is the starting point for graded exercise therapy". Therefore it is possible that the figure "at least one in three people" is actually the GET figure!

Perhaps this is a sign of things to come, as GET is gradually rebranded as pacing 'plus', so it is more acceptable to patients?
We've already seen signs of GET being treated more like pacing: pacing with goals.

 

[Valentijn]

Perhaps this is a sign of things to come, as GET is gradually rebranded as pacing 'plus', so it is more acceptable to patients?
We've already seen signs of GET being treated more like pacing: pacing with goals.

Maybe a good thing if GET ceases to exist as GET and is replaced by pacing.

Maybe a bad thing if it's called pacing to keep us happy, but operates as GET, with any pressure to increase activity levels.

 

[Sean]

Perhaps this is a sign of things to come, as GET is gradually rebranded as pacing 'plus', so it is more acceptable to patients?
We've already seen signs of GET being treated more like pacing. Pacing with goals.

The good ol' Saving Face Dance, in 3 easy steps:

1. Quietly drop the critical defining principle of the original GET requiring patients to completely ignore their symptoms.

2. Carefully conflate this diluted version with the original idea and form of 'pacing'.

3. Hand out large helpings of self-congratulation for being such clever honest brave researchers.

 

[Bob]

AFME has always supported the PACE trial.
...
Their other old CEO Sir Peter Spencer co-authored a letter to the BMJ with Peter White.

I don't particularly want to defend AfME, but just for balance, Peter Spencer did write some quite balanced letters about the PACE Trial results, for example:
"Let's be very clear on this: exercise and talking therapy cannot cure ME. The Pace trial does not say it can. What the study says is that some people who have fatigue as their primary symptom may gain moderate improvements in their physical functioning if they receive a cognitive behaviour or graded exercise programme in a specialist chronic fatigue syndrome/ME clinic."
http://www.scotsman.com/opinion/Letter-ME-myths.6722712.jp

But Action for ME have never clearly disseminated the full results to their readers. (e.g. that no more than 15% of participants responded to treatment, and the poor 6MWDT results.)

I don't have insight into their motivation for being involved in the PACE trial, but they claim the following:
"The charity supported the PACE trial because we wanted pacing – the approach consistently rated as helpful, not harmful, by people with M.E. – to be assessed and legitimised by the NHS.
"We have already expressed our reservations about the current over-emphasis on CBT and GET in the NICE guideline."

They have been pushing CBT and GET (in all it's various guises) for years. Completely in bed with this crowd.

I don't understand why they have recently spent more money investigating GET, when the PACE trial has already demonstrated that it's not effective:
http://forums.phoenixrising.me/inde...fs-probed-via-online-survey-pheby-2013.23613/

But the following text might explain their thinking...
"The findings of the PACE trial contradict the considerable evidence of our own surveys and those of other patient groups.
"Of the 2763 people with M.E. who took part in our 2008 survey, 82% found pacing helpful, compared with 50% for CBT and 45% for GET. Worryingly, 34% reported that GET made them worse.
"A smaller, more recent survey of 273 people with M.E. confirms that, inappropriately applied, graded exercise is still causing harm.
"Whilst these figures are not directly comparable with the PACE results, they cannot be ignored.
"Nor can the fact that, at best, PACE is telling us that the two main therapies currently recommended by the National Institute for Health and Clinical Excellence (NICE) are only moderately effective.
"It’s important to remember that safety outcomes under trial conditions are not representative of what is still happening in some parts of the NHS."
http://www.google.co.uk/url?sa=t&rct=j&q=peter spencer pace trial biomedical&source=web&cd=2&cad=rja&ved=0CDUQFjAB&url=http://www.actionforme.org.uk/get-informed/news/archived-news/our-news/2011/pace-surprising-and-disappointing/index.pdf&ei=7hvAUf7WPPGS0AWfxYCQCw&usg=AFQjCNF5Zm5kvZiLDV0JYvdRGak94hqQCg&bvm=bv.47883778,d.d2k

So perhaps they are relying on their patient surveys, in which quite a high percentage of members said that they found CBT and GET helpful. If I take off my cynical hat for a moment, and give them the benefit of the doubt, perhaps they feel that they can't ignore that information, and perhaps that is why they do not completely dismiss CBT&GET, and perhaps that's why they are trying to figure out why some people find GET helpful, and others find it harmful.

 

[Bob]

Maybe a good thing if GET ceases to exist as GET and is replaced by pacing.

Maybe a bad thing if it's called pacing to keep us happy, but operates as GET, with any pressure to increase activity levels.

I'm not sure if GET will cease to exist entirely, unless they decide to completely rebrand it, with a new name, but that's unlikely considering the investment put into it with the PACE trial. (It's now an accepted NHS treatment.)
But they do seem to be transforming it so that the patient is encouraged to set goals, but always within adaptive safe limits.
Whatever they call it, it will only be a good thing if it promoted as a coping strategy that might help a minority of patients to feel better about their illness, and not promoted as a treatment that reverses the illness.

 

[user9876]

I'm not sure if GET will cease to exist entirely, unless they decide to completely rebrand it, with a new name, but that's unlikely considering the investment put into it with the PACE trial. (It's now an accepted NHS treatment.)
But they do seem to be transforming it so that the patient is encouraged to set goals, but always within adaptive safe limits.
Whatever they call it, it will only be a good thing if it promoted as a coping strategy that might help a minority of patients to feel better about their illness, and not promoted as a treatment that reverses the illness.

It would be interesting to look through a time line of GET descriptions. If GET was a drug they wouldn't be allowed to change the formula of the active component (and the formula would be well defined). Yet I assume different groups have different definitions and also it seems to change over time.

If some patients found a treatment helpful but a significant proportion found it harmful then approval would be hard depending on the relative amounts of harm vs helpfulness. They have failed to identify subgroups that fit either camp if that were the case for a drug I'm not sure if it would be approved. They seem to suggest that harm is down to the way GET is delivered but if a protocol is not well enough defined to be safely reproduced then it is not safe (or not a protocol) hence shouldn't be being rolled out.

We seem to have a major problem in that GET becomes a label being promoted by some research groups but it doesn't have a clear constant semantics and protocol behind it. This will always create confusion in service delivery hence in surveys it remains unclear as to what protocol is being reported on.

 

[user9876]

Here is a section from the PACE trial GET therapists manual where they basically say push activity through any worsening symptoms. They also say that the GET should be so gradual it is unlikely to contribute to setbacks.

Preventing and managing setbacks

CFS/ME setbacks usually involve an exacerbation of their symptoms, leading to a significantly reduced functional capacity. Participants may describe these as a ‘relapse’, or ‘crash’. People with CFS/ME can usually identify an increase in physical activity which may have attributed towards their setback.Sometimes setbacks also appear to be caused by sleep disturbance, a new active infection or emotional distress. It is normal, and likely, that participants will suffer setbacks throughout the GET programme.

If the plan has been undertaken carefully, with a low baseline and small increments as planned, it is unlikely to be the exercise programme that is responsible. However, it is important to ascertain whether any
components of the GET programme may have contributed towards setbacks, and to adapt the
plan immediately to avoid difficulties.
A central concept of GET is to MAINTAIN exercise as much as possible during a CFS/ME setback. This is to reduce the many negative consequences of rest, and to allow the body to habituate to the increase in activity. If activity and exercise is reduced at this time, the boom/bust cycle continues, and the body is not able to desensitise to the increase in activity: which is, of course, an essential component of a graded increase in exercise and activity.

Although it can be difficult to encourage maintenance of exercise despite an increase in symptoms, participants usually are able to understand the reasoning behind this and are often pleased they were able to maintain activity during this time. It is important to explain that although they have an increase in difficult
symptoms, ‘hurt does not equal harm’ (as you would do with somebody wit
h chronic low back pain).

Some participants may be resistant to this approach, and will wish to reduce both activity
and exercise during this time. If they cannot be encouraged to maintain their previous
level of exercise, then encourage them maintain as much as they are able to, and work
towards building up the activity/exercise as soon as possible. Additional support may be
required at this time.

It is helpful to explain the theory behind ma intaining exercise during a setback to
participants BEFORE they have a setback if possible, as while they are symptomatic it
may be more difficult to encourage. It is therefore useful to discuss and review a written
setback plan, outlining useful information to follow in the event of a setback.