Petition: Opposing MEGA

[Jan]

If the people involved in the re-analysis of the PACE trial can manage to get this re-analysis into a paper that is then published in a reputable peer reviewed journal, then the results will have to be seriously considered by NICE if they decide to carry out a 'surveillance review' in 2017 - which may, or may not then lead to an update of the NICE guideline on ME/CFS later in the year

Following the meeting at the House of Lords yesterday,y we are going to seek clarification from NICE as to what is being proposed here - because it is still far from clear from the FoI correspondence

Please remember, as I have pointed out on numerous occasions, that the NICE guideline on ME/CFS was published in 2007 - well before the PACE trial results were announced.

Their recommendations on CBT and GET in 2007 were based on all the other clinical trials involving CBT and GET.

All that has happened since then as far as NICE is concerned, is that the PACE trial results (as published in The Lancet) etc support the position they have taken on CBT and GET

But surely the PACE results must cancel previous studies, being the largest study ever conducted? I can't believe that new patients being diagnosed are being exposed to harm and we aren't doing anything about it. They are not even warned on MEA Fb page,they ar esent to the clinics like lambs to slaughter. I'm not saying don't give them the info regarding clinics, they obviously need to b e diagnosed, but no warning regarding GET & CBT?

 

[lilpink]

I've not been on here for a couple of days so m plyaing catch up and trying to get brain in gear. @lilpink , are you saying that Mindfulness therapy was on the list of unwise interventions drawn up by the RCPsych college members, even high on the list perhaps, and SW or his colleagues at the RCPsych have silenced these psychiatrists from having their say?

Yes indeed, that's exactly what I'm saying, just google - Choosing Wisely RCPsych to access the document (if it hasn't been taken down yet that is ) ! How can anyone trust these people?

 

[Jonathan Edwards]

Thank you for the broad support in principle. Re your reservations:

I don't know about the other types of omics but genomics in particular requires very large samples and 1,000 would not be big enough for that. Chris Ponting (Genomics prof) posted quite a bit on this, saying you won't know the exact size needed til the results are seen, but 10k seems about right
eg here and here

Could you expand on this? I know the biobank recruited quite a lot of patients direct from NHS clinics. I'm also not sure how easy it is for GPs to diagnose (AFAIK, apart fromrunning blood tests, GP diagnosis wasn't independently confirmed), particularly at scale.

What I'd really like to see is an open discussion on this (happy for it to be closed if biobank and other mecfs researchers are involved) to sort out the isses.

I would love to see that too.

Thanks Simon,
My comment was based on following up on Chris Ponting's example of 14,000 patients in a study that included RA and diabetes. But there were 7 diseases so each disease had a cohort of 2,000. For RA, which I know most about, the known genetic associations, DR4 and PTPN22, showed up like a sore thumb. The study seemed to pick up one or two more associations which may dot the i's and cross the t's but the original identification of DR4 and PTPN22 came up on smaller groups. It may be true that if you want to find all the genetic associations you need 12,000 cases but I am a bit sceptical that there is such a thing as all the associations. I suspect that you just get exponentially diminishing returns. To find robust associations that might help in building a theory of pathogenesis I strongly suspect that the sore thumb associations will do.

In fact even in RA the DR4 and PTPN22 associations probably distracted us from building a workable model of disease. Both were thought to point to T cells. This is despite DR4 being first reported as a B cell antigen. Twenty years was wasted looking at T cell responses which turned out to be normal. The story became clear when we found a way to link the known autoantibodies to cytoki ne release mechanisms. PTPN22 was hailed as confirming the T cell theory but a few years later was found to be crucial to B cell receptor editing, which would be the perfect step for risk of autoantibody formation. (Receptor editing is essentially a way of discarding autoantibodies.)

The difference in ME is that we do not have the clues of rheumatoid factor and TNF mediation. So that may be an argument for putting more money into getting a lead from genetics. On the other hand in RA we had solid evidence of a genetic risk long before. In ME would do not even know if there is a genetic risk. Maybe some twin studies need doing at this point. But I am not sure it makes sense to look for all the weak associations that may not help much if you are not even sure there is any association. I do think a genome search is worth doing but my calculation is that a cohort of 1000 would be more cost effective. That is partly because I see little prospect of a clean 12,000 cohort being gathered.

The Biobank recruited not from clinics but from primary care. That has the advantage that it picks up everyone in a defined population who is known to the GP to have ME. If someone is not known to the GP to have ME they are not going to be at a clinic either but there will be lots of patients that the GP is aware of but who do not attend clinics. As I understand it the patients were also vetted by a nurse specialist dedicated to the project to ensure that they conformed to various sets of criteria. I suspect everyone in the cohort was vetted by the same person, so there was consistency. (I have a suspicion that misinformation about this is being circulated - it rather sounds so from your comment!) I would like to see something even more rigorous than this - like the Norfolk Arthritis Register for RA, which identified everyone with RA in a precisely defined population, but I think the Biobank team did as well as they reasonably could. In comparison, asking hospital clinics to send in patients would seem to me to be a recipe for a dog's breakfast. When I presented to my own department on research in ME it was clear to me that my colleagues had all sorts of different ideas about what constituted a CFS patient. I suspect they knew nothing of any disease criteria or weren't interested anyway.

There are professional ME epidemiologists in the UK. I do not see any of their names on the MEGA list.

 

[lilpink]

MEGA was always Esther's baby, and if this is anything to go by facilitated by Holgate. https://meagenda.wordpress.com/2010...presentation-the-future-of-research-in-cfsme/


"Now, the main purpose for this is to be able to look at the different services and benchmark the services but one of the added advantages is what Stephen Holgate is talking about is this already provides a fantastic infrastructure for future research and this is why we’re now able to do the really, really huge genetic studies that I’m going to talk about at the end of this talk."

 

[Esther12]

Yes indeed, that's exactly what I'm saying, just google - Choosing Wisely RCPsych to access the document (if it hasn't been taken down yet that is ) ! How can anyone trust these people?

OT, but here's the link in case of interest:

http://www.rcpsych.ac.uk/docs/Choosing_Wisely_February_2016.docx

Choosing Wisely, February 2016

Following a request from the Academy of Medical Royal Colleges in 2015, our college started a Choosing Wisely campaign. This involved creating a top 5 list of tests or interventions used in psychiatry that we, as the representative body of UK psychiatrists, thought were unnecessary or potentially harmful to patients.

As part of this process we performed a survey of all UK-based college members to obtain your views about which tests or interventions you thought should be on the list. We received a high volume of responses to the survey and have had some good discussions along the way. However, this survey also created concern, as there were interventions on the list that had evidence for being either effective or potentially helpful in diagnosis. In particular, mention must be made about the inclusion of Mindfulness on this list, for which there is a very clear and ample evidence base supporting its use. It was good to be part of a highly interactive process and to stimulate discussion about what is evidence and how do we source it. We are grateful to those who supplied evidence on Mindfulness and other issues. After much political wrangling and hot debate, you will be relieved to hear that we finally managed to agree on a top-5 list of interventions.

The Academy of Medical Royal Colleges will publish our top-5 list in the next few months alongside lists from other colleges. Their aim is to make the issue of overtreatment a prominent national concern. Because of the media sensitive nature of this launch unfortunately we cannot let you know what is on the list yet, but we will inform you as soon as it is released by the Academy.

 

[Chrisb]

It seems to me that there is one measure that could be taken to either give some confidence in MEGA, or totally destroy it.

Given the intended scale of the trial and assuming that things usually take longer than anticipated it might be 10 years before the analyses are in for interpretation. This trial will require strong management and executive capabilities. I watched the video of Stephen Holgate's lecture for Edmesh. He certainly gives the impression that he has the capability to provide the necessary leadership, if we ignore the correspondence with Wessely as a temporary lapse of judgment.

Without wishing to be rude there must be questions about whether he will still be leading the project at that time. A little googling shows that he obtained his first degree in 1968. You can do your own maths. The likelihood must be that at some time over the next, say, five years the project will largely devolve to other leadership. It would help if it were known what the plans were and whether there is an heir unapparent. It would seem to be prudent management to have in place contingency plans for the succession and there can surely be no harm in revealing such plans.

 

[Jo Best]

I think the difference here is that the man and woman are suspected of research misconduct.
I've only been aware of these issues since 2010 when I first heard about the SMILE trial and I have learned not to underestimate their abilities or their power to influence.

So I think we end up with the old saying - you play the ball not the man (or woman).

 

[lilpink]

OT, but here's the link in case of interest:

Personally I don't see this as 'off topic'. The way things are set up to ignore the 'reasonable' or any voice divergent from the psyche / BPS / MUPS (within which ME is subsumed) paradigm should send shivers down the spine of anyone suffering this disease who wants to actually have a hope of getting well (or even slightly better) before they turn up their toes. If this is how they behave to members of their own Royal College (essentially steam roll right over them) then what do we think they'e going to do with MEGA?

 

[Jo Best]

As another patient said: “Burn me once, shame on you. Burn me twice, shame on me.” These charlatans- White, Crawley and friends- have burned us on hundreds of studies, probably substantially caused the early death of many many thousands of ME patients and incalculable suffering The only prudent course to take with any of these insurance lobbyists posing as scientists is to oppose any ME study they propose to undertake! This is a human rights issue. NO MORE!!

Hear hear.

 

[Jo Best]

This seems very logical and acheivable to me that this daydream could become a reality quite easily. After all, Invest in ME were already developing a collaborative of biomedical researchers before the CMRC was formed.

The best outcome is that the rest of the MEGA team reads about the PACE story as told by Julie Rehmeyer and decides they cannot possibly collaborate with the BPS school of thought. They decide to abandon MEGA. In part because they fear their own reputation will suffer, in part because the unethical behaviour disgusts them. They become even more determined to do research on ME/CFS, now knowing how much it is needed. They start looking for alternatives to the CMRC which they now perceive as organization that serves to protect BPS authors interests. They are invited to IiME and get involved in a new project, outside of the sphere of influence of the BPS school.

A little daydreaming.

 

[charles shepherd]

But surely the PACE results must cancel previous studies, being the largest study ever conducted? I can't believe that new patients being diagnosed are being exposed to harm and we aren't doing anything about it. They are not even warned on MEA Fb page,they ar esent to the clinics like lambs to slaughter. I'm not saying don't give them the info regarding clinics, they obviously need to b e diagnosed, but no warning regarding GET & CBT?

Jan

As I have already tried to explain on several occasions - but obviously failed:

1 The PACE trial results were NOT used to prepare the 2007 NICE guideline

2 The recommendations in the 2007 NICE guideline on CBT, GET and Pacing are based on clinical trials published prior to 2007 and analysed in the York Systemic Review - which formed a key part of the background scoping for the NICE guideline

3 At present, and until the re-analysis of the PACE trial results have been published in a reputable peer reviewed journal, NICE regards the PACE results as sound - in exactly the same way that The Lancet is standing by their decision to publish the results

4 If the situation changes, and the re-analysis results are published next year, and/or The Lancet retracts the PACE paper then NICE will have to take this evidence seriously

I know you don't like what I am saying but please don't shoot the messenger!


A summary of the MEA patient evidence (278 pages) report on CBT, GET and Pacing, along with MEA statements on these three approaches to management, is featured prominently on the Home page of the MEA website:

http://www.meassociation.org.uk/how-you-can-help/introduction-to-our-cbt-get-and-pacing-report/
MEA recommendations regarding CBT, GET and Pacing from the Home page of the MEA website:

REPORT CONCLUSIONS AND RECOMMENDATIONS
Cognitive Behavioural Therapy (CBT)

We conclude that CBT in its current delivered form should not be recommended as a primary intervention for people with ME/CFS.

CBT courses based on the model that abnormal beliefs and behaviours are responsible for maintaining the illness, have no role to play in the management of ME/CFS and increase the risk of symptoms becoming worse. The belief of some CBT practitioners that ME/CFS is a psychological illness was the main factor which led to less symptoms improving, less courses being appropriate to needs, more symptoms becoming worse and more courses being seen as inappropriate.

Our results indicate that graded exercise therapy should form no part of any activity management advice employed in the delivery of CBT, as this also led to a negative impact on outcomes.

There is a clear need for better training among practitioners. The data indicates that lack of knowledge and experience had a direct effect on outcomes and remained a key factor, even where courses were held in specialist clinics or elsewhere given by therapists with an ME/CFS specialism.

However, our results did indicate that, when used appropriately, the practical coping component of CBT can have a positive effect in helping some patients come to terms with their diagnosis and adapt their lives to best accommodate it.

CBT was also seen to have a positive effect in helping some patients deal with comorbid issues – anxiety, depression, stress – which may occur at any time for someone with a long-term disabling illness.

An appropriate model of CBT – one that helps patients learn practical coping skills and/or manage co-morbid issues such as those listed above – could be employed, where appropriate, for ME/CFS as it is for other chronic physical illnesses such as multiple sclerosis, Parkinson’s disease, cancer, heart disease, and arthritis and we recommend all patients should have access to such courses as well as access to follow-up courses and/or consultations as and when required.

Graded Exercise Therapy (GET)

We conclude that GET should be withdrawn with immediate effect as a primary intervention for everyone with ME/CFS.

One of the main factors that led to patients reporting that GET was inappropriate was the very nature of GET itself, especially when it was used on the basis that there is no underlying physical cause for their symptoms, and that patients are basically ill because of inactivity and deconditioning.

A significant number of patients had been given advice on exercise and activity management that was judged harmful with symptoms becoming worse or much worse and leading to relapse. And it is worth noting that despite current NICE recommendations, a significant number of severe to very severe patients were recommended GET by practitioners and/or had taken part in GET courses.

The other major factor contributing to worsening symptoms was the incorrect belief held by some practitioners that ME/CFS is a psychological condition leading to erroneous advice that exercise could overcome the illness if only patients would ‘push through’.

We recognise that it is impossible for all treatments for a disease to be free from side-effects, but if GET was a licensed medication, we believe the number of people reporting significant adverse effects would lead to a review of its use by regulatory authorities.

As a physical exercise-based therapy, GET may be of benefit to a sub-group who come under the ME/CFS umbrella and are able to tolerate regular and progressive increases in some form of aerobic activity, irrespective of their symptoms. However, identifying a patient who could come within that sub-group is problematic and not possible at present.

Some patients indicated that they had been on a course which had a gentle approach of graded activity rather than a more robust and structured approach of graded physical exercise. There were some reports that patients were told they should not exercise when they felt too unwell to do so. These led, for some, to an improvement in symptoms or to symptoms remaining unaffected.

However, we conclude that GET cannot be regarded as a safe and effective form of treatment for the majority of people with ME/CFS. The fact that many people, including those who consider themselves severely affected, are being referred to specialist services for an intervention that makes them either worse or much worse is clearly unacceptable and in many cases dangerous.

GET should therefore be withdrawn by NICE and from NHS specialist services as a recommended treatment with immediate effect for everyone who has a diagnosis of ME/CFS. This advice should remain until there are reliable methods for determining which people who come under the ME/CFS umbrella are likely to find that GET is a safe and effective form of management.

Pacing

Pacing was consistently shown to be the most effective, safe, acceptable and preferred form of activity management for people with ME/CFS and should therefore be a key component of any illness management programme.

For some, improvement may be a slow process so, whilst they may be somewhat better by the end of a course, the improvement is not enough to take them into a better category of severity for some time, perhaps not until they have self-managed their illness for a few years.

The benefit of Pacing may relate to helping people cope and adapt to their illness rather than contributing to a significant improvement in functional status. Learning coping strategies can help make courses more appropriate to needs even if they do not lead to immediate or even longer term improvement in symptoms. Importantly, it can prevent symptoms from becoming worse.

Pacing can be just as applicable to someone who is severely affected, as to someone who is mildly or moderately affected, although additional measures need to be taken to ensure that a person who is severely affected has equal access to services.

As with CBT, there must be better training for practitioners who are to deliver such management courses. Proposed increases in activity, both mental and physical, must be gradual, flexible and individually tailored to a patient’s ability and circumstance and not progressively increased regardless of how the patient is responding and therapists must be taught to recognise that.

All patients should have access to suitable courses, follow-up courses and/or consultations as and when required.

Note: Please see Sections 4 and 5 for our full conclusions and recommendations. Caveats are set out in Section 6.

OUR THANKS
We are indebted to Ba Stafford, Dr Charles Shepherd and Neil Riley for their work in producing this Report. Further acknowledgements are given on page 94 of the Report.

 

[charles shepherd]

MEGA study

New blog from Professor Hugh Perry >>

https://www.change.org/p/support-th...ation-to-major-uk-research-funders/u/18265562

Professor V Hugh Perry is Professor of Experimental Neuropathology within Biological Sciences at the University of Southampton. He is also Chair Neuroscience and Mental Health Board. MRC, UK; Visiting Professor in the College of Medicine & Veterinary Medicine. University of Edinburgh. Hugh is a member of the UK CFS/ME Research Collaborative Executive Board and is supporting the development of MEGA.

 

[Jo Best]

I think this shows how capable are patients of engaging directly with researchers, with the benefit of the various forms of communication available on the internet today. Just to add that there was no option on the poll to vote no confidence (that had to be done by selecting 'other') so the counter-petition provides that clear option.

From #MEAction UK Facebook page

https://www.facebook.com/MEActNetUK/posts/1690444127940210

 

[slysaint]

Although this is a bit out of date and put together a few years ago I think it would be important reading material for any UK scientists involved with the MEGA project, not with a view to putting them off but quite the opposite. Namely to show how the plight of ME sufferers is not just down to lack of research, but the willful and 'vexacious' actions of those who are now regarded as the 'experts'.

How to Make a disease Disappear
http://www.meactionuk.org.uk/MW/2010/magical-medicine_hooper_feb2010.pdf

 

[Jo Best]

I think the CMRC was set up to protect and serve the BPS school.

A quote by Prof Stephen Holgate, chair of MEGA from an old copy of Perspectives (date unknown):

http://www.nature.com/articles/nrn3087.epdf?referrer_access_token=FtyxhnojvctriyuAKuuoVNRgN0jAjWel9jnR3ZoTv0PCC0--nFSrLFO81i3ZUnjqhKK63miDucfglaZycG9a0HzhM915nD_xPNk9XNaiRU_skUulxrYWYPxJ3Huo9qWPnY_tCwdY2VKsSUhisQrOQ1qoNQDQ_WXKvFTJDLSdQ0Grg65p_CayB9Ot_tFfWxQFOieqrNl42Dc2uVwcwxmwCvgYsyLlFJo0fm3E3z6UjCo=&tracking_referrer=solvecfs.org

When asked the question:

How strong is the evidence that viral infections and/or immune dysregulation play a role in the aetiology of CFS?

Prof Stephen Holgate answered:

The current understanding of the syndrome of CFS/ME is that it has an external environmental or biological trigger, such as chemical exposure or a virus, but that psychological and social factors are important in perpetuating the illness.

Does he still adhere to this belief?

 

[Esther12]

2 The recommendations in the 2007 NICE guideline on CBT, GET and Pacing are based on clinical trials published prior to 2007 and analysed in the York Systemic Review - which formed a key part of the background scoping for the NICE guideline

3 At present, and until the re-analysis of the PACE trial results have been published in a reputable peer reviewed journal, NICE regards the PACE results as sound - in exactly the same way that The Lancet is standing by their decision to publish the results

4 If the situation changes, and the re-analysis results are published next year, and/or The Lancet retracts the PACE paper then NICE will have to take this evidence seriously

I've gained some understanding of the frustrating way that many in UK medicine can try to come up with reasons for not thinking critically and looking at the evidence, but this is a bad thing that I think it's legitimate for patient groups to push back against.

It shouldn't require a peer reviewed paper for NICE to take concerns about the PACE trial (and earlier trials of CBT/GET) seriously. They should be taking their responsibilities seriously, and that requires them to recognise that the current systems around medical research are less than ideal, and that flawed research can be picked apart by patients on blogs, in e-mails, wherever. If NICE want to assert that the way the PACE results were presented in the Lancet etc is sound, then they should be willing to defend that assertion against the many criticism made by others.

I realise that they will want to avoid doing this... but it's their job to critically assess the evidence and ensure that money isn't being wasted on treatments that are of no real value.

I know that I can seem idealistic on things like this, but there should be room for pursuit of the ideal of patients being given accurate information on treatment efficacy regardless of the politics involved. Pushing for those in authority to justify actions with evidence based arguments seems like a reasonable thing to do. If they're not willing to engage with the details of patient concerns just because they have not gone through peer-review, that rather undermines their claims about the importance of patient and public involvement in their work!

 

[Jo Best]

I agree that the petition could equally have been no confidence in the CMRC but I think some CMRC members were saying that MEGA was an independent alliance and also t was MEGA that set up the petition.

If this cannot be done I think there needs to be a vote from patients, can they still proceed if there is a vote of no confidence in the CMRC? Maybe this should have been done instead of OMEGA, start at the top.

 

[Marco]

In ME would do not even know if there is a genetic risk. Maybe some twin studies need doing at this point. But I am not sure it makes sense to look for all the weak associations that may not help much if you are not even sure there is any association.

I was thinking this may be off-topic but maybe not as it's relevant to the value of 'big data'. If there was some genetic predisposition would you necessarily expect that to result in the same group of symptoms and therefore the same diagnosis?

I'm thinking of fairly recent genomics findings that alterations to a single gene may underpin autism spectrum disorder, attention deficit-hyperactivity disorder, bipolar disorder, major depressive disorder, and schizophrenia.

Perhaps a more useful initial approach to big data would be epidemiological - e.g. something like scanning the scandanavian registries to see if a ME/CFS diagnosis clusters with anything else.

 

[batteredoldbook]

Pwme should not support researchers who reserve judgement on PACE. Until the fundamental methodological issue addressed, I think you are likely to waste both time and money on MEGA.

 

[Simon]

Thanks Simon,
My comment was based on following up on Chris Ponting's example of 14,000 patients in a study that included RA and diabetes. But there were 7 diseases so each disease had a cohort of 2,000. For RA, which I know most about, the known genetic associations, DR4 and PTPN22, showed up like a sore thumb.

I do think a genome search is worth doing but my calculation is that a cohort of 1000 would be more cost effective.

Thanks, Jonathan.

I'll ask Chris if he wants to comment. Meanwhile, Hugh Perry has just blogged about Genomics in Alzheimer's disease, which may be relevant. the APoE genetic connection has been known for a long time (the ultimate genomics sore thumb), but more recent and larger GWAS studies have revealed more genes at play: often while individual genes have a small effect, they cluster to highlight particular pathways (so the aggregate effect is important, even if the individual gene effect is trivial). If mecfs is heterogenous, as seems likely, that would also require a bigger sample size - and the need to identify subgroups has always explicitly been part of the logic for a large sample.

The Biobank recruited not from clinics but from primary care. That has the advantage that it picks up everyone in a defined population who is known to the GP to have ME. If someone is not known to the GP to have ME they are not going to be at a clinic either but there will be lots of patients that the GP is aware of but who do not attend clinics. As I understand it the patients were also vetted by a nurse specialist dedicated to the project to ensure that they conformed to various sets of criteria.

Ah, I was confused because the 2014 progress report says:

Once ethics approvals were granted, we began inviting potential participants through primary and secondary health services in East of England and London in March 2012.

Is a secondary health service different from a clinic? I also wasn't sure if the GP diagnoses were independently validated by CFS clinic consultants, or if there was any psychological assessment (as is mandated in most definitions). But it struck me a detailed discussion between MEGA and the biobank would be productive given the overlap in their approaches.

When I presented to my own department on research in ME it was clear to me that my colleagues had all sorts of different ideas about what constituted a CFS patient. I suspect they knew nothing of any disease criteria or weren't interested anyway.

MEGA would have a standard operatinng procedure precisely to tackle this issue.