BMJ comments on new PACE trial data analysis

[Aurator]

But unless we do something to test out the theory of pacing we are just going to be responding to yet more studies - and there are more in the pipeline - which claim that GET is the best form of activity/energy management for ME/CFS

It strikes me that our efforts need to be directed first and foremost into making what is clearly a far from level playing field more level. KCL studies of the sort we are currently responding to apparently have no problem being funded, and it seems inevitable that a steady stream of research findings of the same specious kind will continue to monopolize the limelight and the attention of medical practitioners for the foreseeable future.

How can we hope to compete on equal terms, however well-founded our own countervailing theories may be, if we do not have comparative access to funding and the same licence to publish? Surely this basic inequality of opportunity among the different groups of researchers should be taken into account when decisions come to be made on what is the best treatment for patients. Is it not all too apparent to the decision makers that the current very one-sided research emphasis is a serious weakness in the search for a fuller understanding of what all sides are agreed is a multi-faceted illness?

 

[charles shepherd]

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Charles Shepherd wrote: "But unless we do something to test out the theory of pacing we are just going to be responding to yet more studies - and there are more in the pipeline - which claim that GET is the best form of activity/energy management for ME/CFS"


Surely there is enough research already existing to refute GET as treatment for ME. Any pacing trial would require pacing to be tested over a long period of time. Who would fund a pacing trial? And is a pacing trial really the research priority at this point?

Are we prepared to hold our collective breath for yet another decade, hoping that a pacing study would validate pacing? The decades are slipping by.

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You may be convinced that there is enough evidence to refute GET as a treatment for ME/CFS but out in the real (medical) world this is NOT what my medical colleagues, or the people who prepare the NICE guideline, or the insurance companies who try to deny payments to people with ME/CFS because they will not undertake GET etc etc believe.

I'm not saying that a robust assessment of pacing that the UK medical profession would take seriously is a number one research priority - but it would be quite high on my list!

As to who would pay - as I've already indicated this is the sort of expensive research that the charities such as MEA could only HELP to fund. Someone would have to submit an application to the MRC, or a big funder such as The Wellcome Trust.

 

[Sasha]

But unless we do something to test out the theory of pacing we are just going to be responding to yet more studies - and there are more in the pipeline - which claim that GET is the best form of activity/energy management for ME/CFS

I don't like to add to the pile-on, @charles shepherd, but I recently looked indirectly at the meta-analytic evidence for GET provided in the P2P draft and supporting documentation.

Almost all GET trials have been Oxford. P2P recommends that Oxford be ditched, and many patients (me included) who have written in, and CFSAC, recommend that all Oxford trials be ditched because they just don't tell anyone anything about ME (as opposed to Oxford 'chronic fatigue').

If you take out the Oxford trials you're left with Moss-Morris - a trial with 25 patients and 24 controls and a barely statistically significant effect. That's it.

Add to that all the other criticisms - lack of blinding, lack of objective measures, the huge catalogue of problems with PACE, the fact that even PACE shows that GET fails, and there's simply no case to answer.

And yet we are not heard.

The issue of GET appears almost beyond rational debate in the current climate. Adding a pacing trial to that mix won't help, because it's not an inherently curative approach and will be at best a very weak effect for the vast majority of patients. It won't be seen as an improvement on GET. And we patients don't want weak effects - we want big ones.

What will really get rid of GET is a solid understanding of the biological mechanisms involved in ME and/or a successful trial of a pharmacological intervention such as Rituximab or Ampligen. Once that happens, the paradigm will shift and GET will either be just left behind or its powerbase so weakened that our rational attacks are finally heard and it's ditched.

I understand that the MEA constantly pushes for biomedical research and I'm very grateful for that. I think that's the way to go, though, not a trial on pacing.

 

[Sasha]

You may be convinced that there is enough evidence to refute GET as a treatment for ME/CFS but out in the real (medical) world this is NOT what my medical colleagues, or the people who prepare the NICE guideline, or the insurance companies who try to deny payments to people with ME/CFS because they will not undertake GET etc etc believe.

We crossed - and I agree on this particular point, that evidence and argument has so far failed to dislodge GET. But so would a pacing trial.

 

[Wildcat]

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Trudie Chalder Video Interview on CBT and GET

Short interview with Trudie Chalder, not clear where from, fairly recent. In which she claims that “the patient organisations” have an open mind about treatments (CBT/GET) and work with her and her team. We know that for the duration of the PACE Trial (2004-2011) Action for ME (AFME) collaborated with Trudie Chalder and White and Sharpe on the PACE Trial.

A start would be to refute Trudie Chalders statements. AFME and the Kent and Sussex CFS/ME Society supported the PACE Trial but none of the other patient organisations did. Its totally false to state that patient orgs are willing to work with Trudie Chalder on CBT and Graded Exercise.




http://www.yourepeat.com/watch/?v=_PuGKWIXWdQ

Interviewer: “How important is the opinion of Patient Groups and how confident are you that you can bring them on board with this?”

Trudie Chalder: “I think we have been working very closely with the Patient Organisations over a number of years both in terms of this trial and in our clinic…… People in the Patient Organisations have an open mind and that they are willing to work with us …. they have been involved in terms of the treatments in this trial…..”
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[Kati]

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Trudie Chalder Video Interview on CBT and GET

Short interview with Trudie Chalder, not clear where from, fairly recent. In which she claims that “the patient organisations” have an open mind about treatments (CBT/GET) and work with her and her team. We know that for the duration of the PACE Trial (2004-2011) Action for ME (AFME) collaborated with Trudie Chalder and White and Sharpe on the PACE Trial.

A start would be to refute Trudie Chalders statements. AFME and the Kent and Sussex CFS/ME Society supported the PACE Trial but none of the other patient organisations did. Its totally false to state that patient orgs are willing to work with Trudie Chalder.



http://www.yourepeat.com/watch/?v=_PuGKWIXWdQ

Interviewer: “How important is the opinion of Patient Groups and how confident are you that you can bring them on board with this?”

Trudie Chalder: “I think we have been working very closely with the Patient Organisations over a number of years both in terms of this trial and in our clinic…… People in the Patient Organisations have an open mind and that they are willing to work with us …. they have been involved in terms of the treatments in this trial…..”
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Gag... i'm feeling sick. Which planet is she from?

 

[Aurator]

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People in the Patient Organisations have an open mind
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I'd say that's an accurate assessment; most of the patient organisations do, in my experience, have an open mind. What the speaker forgot to mention was the degree to which her own particular research team have or don't have an open mind.
I couldn't help noticing that when she said "I think (she doesn't sound so sure) we've been working very closely with the patient organizations..." she suddenly dropped her gaze and lost eye-contact with the interviewer. Would anyone care to comment on the possible implications there about her belief in the truth of what she was saying?

 

[Jonathan Edwards]

Jonathan - BMJ rapid responses are all moderated before they appear. And I suspect the moderater may be having a day off today!

Yes, I am hoping that this is the reason why it has not appeared, rather than a judicious decision not to get involved in a libel case.

I agree that there are huge problems in designing some form of trial that is going to produce a meaningful assessment of the safety and efficacy of pacing - however we decide to define it. But unless we do something to test out the theory of pacing we are just going to be responding to yet more studies - and there are more in the pipeline - which claim that GET is the best form of activity/energy management for ME/CFS

Now, Charles, I didn't actually say do nothing, although I admit I got close to it. I was thinking that we need a new methodology that mitigates the placebo problem. I need to think about this more in this context but I have had some thoughts about this for other reasons.

One thing that a good pharmacology team will always do is a dose response study. An important advantage of this is that it defuses the placebo issue. The frailty of human nature simply cannot distinguish between four different doses in emotional terms - so you tend to get a cleaner result. The prediction being tested is also distanced from wishful thinking because it is just that the groups should form a credible pharmacological curve. Apart from odd bellshapes there has to be a good reason for not getting a sigmoid shape.

The fact that GET cannot be blinded might still make any attempt at dose response weak. Moreover, dose variation with exercise might be difficult to achieve usefully and we would not know quite what curve to expect. It could easily be bellshaped, but asymmetrical. So things are not that easy.

But thinking more broadly I wonder if one way to mitigate the placebo response is to exclude 'therapy' from the study. A placebo response is generally considered to be a positive response to a therapeutic intervention involving a carer (or team) and a patient. The mechanism may include complicated things like patients telling the carer what they want to hear but it is all about therapy. So maybe the thing is to have a trial in which there is no therapeutic act as such - because there is no distinction between patient and carer. This needs thought, but if a trial is set up by a consortium of patients rather than carers and especially if assessment is delegated to people hired to score outcomes who have no prior involvement in any therapeutic training and a spectrum of self-management options are drafted over a range for which nobody can decide what they really think would be best, then we might begin to get a study that at least has no reason to be biased, even if bias is still possible. And clearly it needs more thought than that but to be honest I am not sure it is any more insoluble than the problem I had in designing an RA rituximab trial on 5 cases that would convince a drug company to take interest if there was a major effect to be found. I broke all the rules but in doing so got the effect needed! The key thing is to have a study that does not involve any therapists.

 

[Jonathan Edwards]

Or to be a bit simpler. Do a self- organised pacing study with options ranging from more or less GET to the other extreme but precisely calibrated and see if you get a sigmoid or a bellshaped curve.

 

[lansbergen]

Staying withig ones activity limits is a skill patients must learn themselves. No therapist can do that for them.

 

[alex3619]

It strikes me that our efforts need to be directed first and foremost into making what is clearly a far from level playing field more level. KCL studies of the sort we are currently responding to apparently have no problem being funded, and it seems inevitable that a steady stream of research findings of the same specious kind will continue to monopolize the limelight and the attention of medical practitioners for the foreseeable future.

This is the phenomenon called Zombie Science. Funding poor studies to suit corporate or political agendas distort the science base.

 

[green_monster]

Good day everyone.

I have had ME for a long time and I am angry. I am sick to the back teeth of this entire subject. I really want to swear now (but I won't). This illness has cost me everything over the years. Not just my health, but also my partner, my house, my friends, my career, my pension, my dignity, the whole damn lot. Here is what I have to say about this.

Stop falling into the trap set by the psychiatrists and their media buddies. Arguing about PACE will cause nothing but damage and heartache. No matter how you argue they will just turn around and tell you that PACE is brilliant. There is nothing to be gained by telling them it's not brilliant. They are not interested.

NICE and the psychiatrists and the British media and the Science Media Center and most doctors and most politicians and most people in Britain think ME is a psychiatric biopsychosocial exercise fear cuckoo illness belief.
We are all psychodeniers. End of story.

The best way to refute PACE is to present evidence that ME is a bog standard physical illness, on a par with MS or RA or Crohn's or whatever.

There are many hundreds of published papers that provide evidence that ME is a complex and serious neuroimmune illness. A physical illness.

It is not ideal for patients to do this refuting. We are 'mentally ill' remember. Imagine how it looks to the media, doctors, politicians, the general public. A bunch of mental psychodeniers saying we are not mentally ill. It isn't a good look. It doesn't help that most of us are seriously disabled.

We need able bodied, non-mad, non-loopy people to be our advocates. Here is a great suggestion that I bet nobody has thought of before. The best people to present all those hundreds of biomedical research papers are doctors and scientists. You write the damn things so it is your job to make sure the right people read them. In this case, the media need to read them. It isn't my job to do this. I'm ill. I'm a patient. All those papers are not much use right now, because they are hidden away in journals.

What is so hard about that? Why can't 50 doctors and scientists present this research to the media? It doesn't have to be a criticism of PACE or psychiatry. It doesn't have to be a ten billion page document that takes 10 years to write. Just list about 200 papers and get 50 people to sign it. How hard can that be?

There are some esteemed doctors and scientists interested in this illness. I'll give you a clue.


Dr Ron Davis - Stanford - One of people who made the Human Genome Project happen. Runs one of the most advanced genetics labs in the world. His son happens to have ME.

Dr Ian Lipkin - Columbia - Runs one of the most advanced pathogen labs in the world. Eats Ebola for breakfast. Spent $200,000 of his own money on ME research. He's committed to the fight.

Dr Michael Houghton - Alberta - co-discoverer of Hepatitis C virus. Lasker Award winner. Working on ME biomarker.

Dr Mario Capecci - Utah - Lasker Award and Nobel Prize. Neurology and genetics. Say no more.

Dr James D Watson - Nobel Prize - He discovered DNA. Say no more.

Prof Warren Tate - Otago - Rutherford Medal. Alzheimers work. His daughter has ME by the way.

Dr Mark Davis - Stanford - Runs a world leading Immunology lab. Currently his biggest single workload happens to be ME.

Prof Emeritus Jonathon Edwards - UCL - RA/B Cells/Rituximab

Dr Shepherd - obviously


Need I go on? How f***ing hard can it be to do the following-

1) Knock up a thoughtful cover letter
2) List 200 decent research papers
3) Get 50 top people to sign it
4) Send it to anybody who will listen. British newspapers and the biased BBC would be a good start. Followed by NICE.

Don't waste too much time trying to dismantle PACE. Trying to take PACE apart has been tried repeatedly and failed repeatedly. Psychiatrists will just hide behind the 'science' and their media allies and make people with ME look stupid. It will be impossible to get 50 experts to agree on what to write anyway. They will never agree on just how to criticize PACE.

Some letters or statements from notable individuals that criticize PACE would be useful, but these should be in addition to the 200 research papers. Present the extensive biomedical evidence as it stands now and PACE will start to discredit itself and hopefully self destruct.

Even journalists who are as thick as pig shit will perhaps be slightly curious when they start getting letters signed by Nobel Laureates explaining that there have been hundreds of studies going back decades. I'll tell you a secret now. People like White, Simon Weasel, and Truudie won't be telling journalists like Hanlon about all those biomedical papers. They won't be telling the journalists about Nobel Laureates being involved in this. The time for gentle academic discussions with psychiatrists is long gone, if it even ever existed. Just ignore them. Have nothing to do with them. Just produce a heap a research evidence and give it to the people who need it, such as journalists.

So who is going to volunteer to do this? Anybody with the stature and credibility to organize this? It would be preferable if someone like a scientist or a doctor went around getting signatures I imagine. Not some mental scumbag off the street like me. I don't mind helping to the best of my ability, but I'm not a doctor or a scientist. But I'll tell you what. If no one else does this, I'm going to do it myself.

I'll just finish by saying that this isn't a dig against Dr Sheperd or Prof Edwards. The both of you do great work. This is most certainly a deliberate dig at the medical profession, the media and the politicians though. Failures, one and all.

Thanks, Green Monster.

PS Green Monster isn't my real name. Call me Fred if you like.

 

[Esther12]

The best way to refute PACE is to present evidence that ME is a bog standard physical illness, on a par with MS or RA or Crohn's or whatever.

There are many hundreds of published papers that provide evidence that ME is a complex and serious neuroimmune illness. A physical illness.

A lot of those papers aren't very good, and they haven't even convinced me. Also, many can be adopted into a biopsychosocial framework if you fail to recognise the problems with PACE. I can see the emotional appeal of your tactic, but I just don't think that is where the strongest arguments lie, and in the end I think that the best tactic is to follow the evidence and be as intellectually honest as possible regardless of the short-term discomfort this may cause.

 

[Esther12]

Or to be a bit simpler. Do a self- organised pacing study with options ranging from more or less GET to the other extreme but precisely calibrated and see if you get a sigmoid or a bellshaped curve.

That's interesting. I'd still have some political concern about experimenting with this approach on ME/CFS (I've been left feeling pretty cautious about this stuff), but that would address a lot of obvious sources of bias.

 

[Jonathan Edwards]

A good rant Green Monster, and some very fair points. Let me try to justify my current position.

I agree that PACE is tedious and not the priority. I don't spend that much time thinking about it in comparison to trying to think of useful research but I think the present situation does merit a response, and I have sent one to the BMJ - took me 40 minutes.

I am less pessimistic about the opinions of UK doctors who are committed to looking after PWME (as opposed to a large number who run a mile). A have talked to several since I got involved with IiME. In general they are just as receptive to the idea that there might be biological treatments as they are for CBT. They would welcome anything that would help. So I am not convinced that comments need fall on deaf ears. When I was looking for clinicians who might be interested in being involved in a drug trial nobody actually said no thanks. As far as I can see nobody has really challenged PACE in an open arena. I think that is worth doing.

So I entirely agree that the priority is biological research. Where I differ is in the interpretation of your sentence : There are many hundreds of published papers that provide evidence that ME is a complex and serious neuroimmune illness. A physical illness.

If there was convincing evidence for ME being a neuroimmune illness from research studies I would not be on this list. I would be writing philosophy and birdwatching and leaving ME research to the people who were solving the problem. The only reason I am here is that so far I do not think any of the published evidence is hard enough to rely on. The evidence of neuroimmune dysfunction to my mind comes from the clinical disease. Research has not so far reliably supported that. There is a desperate need for harder evidence. And think Ian Lipkin would probably agree with me. At the 2014 IiME colloquium about 40 scientists sitting around a table murmured in unison to my question 'what do we know for sure' the answer 'nothing'. That does not put me off because I have been in a similar situation before, but it needs to be confronted.

If the 200 papers showed hard evidence then I would readily put my name to a letter, except that I would not need to since they would speak for themselves. What I think I can do is call into question the assumption that the behavioural aspect is better documented than the biological one. I am not convinced that this has been done before by someone in my position. I am disinterested - I have no reason to be attacking something as a competitor. I am regarded as one of the most successful clinical academics of my generation in the UK. I have a track record in immune disease. I am retired so I can say what I like. I can say that trials of CBT and GET are so far uninterpretable and if anything strongly suggestive of no useful effect. I can say that there are a number of interesting hints about possible biological pathways in ME but that we need better evidence. Pretending we have hard evidence now would simply invite justified denial. That is why nobody has written that letter yet.

 

[green_monster]

Ok Esther 12, I give up. You say follow the evidence. Which evidence is more plausible? The six minute walking test in PACE or some of the other papers that you think are rubbish? You know, like the Rituximab trial, or the gene studies by Ron Davis, or the cytokine studies by Lipkin and others, or the MRI studies showing brain inflammation. These are some of the very best scientists in the world. If their research papers can't be trusted then no papers in the world can be trusted. Lets just ban all medical research right now and save the money and hassle.

I can't for the life of me see how some kind of inverse version of the PACE trial will cancel out the PACE trial. You say that many of the papers can be adopted into a biopsychosocial framework. Well, I imagine some inverse version of the PACE trial will be excellent material to adopt into a biopsychosocial framework. It will be the easiest thing in the world for a psychiatrist to regard "pacing" as something that counts as biopsychosocial.

 

[eafw]

As far as I can see nobody has really challenged PACE in an open arena. I think that is worth doing.

Yes. We can, and need to, fight this on two fronts. One is the research itself and the other is the challenge to the harm that is being done by the PACE and the psych proponents. That harm being lack of good or inappropriate treatments, the vilification of patients, the muddying of definitions - "chronic fatigue" - which also means we have fewer decent studies being done on ME as a neuroimmune condition.

 

[eafw]

I can say that there are a number of interesting hints about possible biological pathways in ME but that we need better evidence. Pretending we have hard evidence now would simply invite justified denial.

By hard evidence do you mean bigger and repeated studies or that the studies that have been done so far are in and of themselves poor science, or too much is still speculative ?

I mean there is stuff out there about the biological process, what do you think is lacking ?

 

[Jonathan Edwards]

By hard evidence do you mean bigger and repeated studies or that the studies that have been done so far are in and of themselves poor science, or too much is still speculative ?

I mean there is stuff out there about the biological process, what do you think is lacking ?

Mostly it needs replicating. There are so many experiments being done that a proportion of the results are bound to be flukes. A useful observation needs to be replicable. And where trials are done they need to be adequately designed.

 

[green_monster]

Thanks for that thoughtful and considered reply to my bit of a rant, Prof. Edwards, especially at this time of night. I do appreciate that you often spend unsociable hours at weekends dealing with the likes of me. Thanks.

Ok, maybe 200 papers is overdoing it a bit, that's obviously a random number. I do know that on the IACFS/ME Clinical Primer document there are dozens of papers cited, and lots of doctors and scientists have put their names on that document. They are not saying that they know what the illness is, but they are saying that there is strong evidence to suggest that a physical illness does in fact exist in some shape or form.

The point I'm trying to make is that the evidence suggesting that this a 'physical' illness far outweighs the evidence that this is a 'biopsychosocial' illness. I accept your point that there is no hard evidence that this is a neuroimmune disease. There is also no hard evidence that this is psychiatric illness fear belief. I find it hard to understand how we find ourselves in the situation where the default position is that the psychiatric version is correct and any other version is automatically wrong. Is it just because the psychiatrists claimed it first? In a case like this where there isn't a definitive answer as to whether this is a 'physical' or 'mental' illness, at the very least the two should be considered equally plausible.

Maybe we should just send copies of the IACFS/ME Clinical Primer to the journalists and be done with it. It just seems such a shame that there are so many world class scientists and clinicians working on this illness, including yourself Prof Edwards, yet hardly anyone on the outside seems to notice or care. The media are clueless and are being used as a propaganda tool. NICE kicked ME/CFS into the long grass for 5 years, said nothing interesting was happening. Wasn't there something about a Judicial Review into PACE a while back. I really hope this current research collaborative gains some traction (and funding), because I'm sick and tired of waiting, year after year, now it's decade after decade.

Those newspaper articles the last few days haven't done me any favours, lets put it that way. People who I thought I could trust have read that trash and now think I'm just tired and like to moan. You know, bit of an attention seeker. I haven't got the heart to show them all the bits of paper from various hospitals that show all kinds of physical abnormalities. Bet that story rings a few bells on here. I really doubt I'm the only one. Anyway.

Thanks again for all the work you do Prof. Edwards. It's a unique thing to have someone of your seniority and experience sharing your thoughts and ideas. It's a real eye opener. Cheers, and best of luck with your Rituximab work.