UK Parliamentary debate today - Thursday 24th January 2019

Yes, a lot of people do seem to have a blind spot for human nature - perhaps particularly psychiatrists!

Maybe if you are expecting a debate of this sort you should slip in a trick question before hand, like 'how was your holiday'. I bet they will say 'yes, very nice thanks', or even 'wonderful'. But closer interrogation might reveal that they didn't really mean that at all.

 

The report from the so-called Gibson Inquiry, by a group of parliamentarians, as I recall has some useful info on issues relating to MRC funding.

It wasn’t perfect but I think looking for perfection wasn’t necessarily the optimum strategy to use. For example, it said it affected children from five up. Some people complained that younger children could be affected but it wasn’t written by a group of health professionals so I doubt it would have much effect on clinical decisions.

 

It is an Australian survey.

 

Ah, my bad. But there was one shared recently from ME Association (I think) that had similar numbers. There was another one from Norway as well, I think? But somewhere around 1K respondents as well.

We're really lacking in updated data here. Bits and pieces everywhere just isn't good enough. Can't fix what you don't measure...

 

I think you are right on this. I suspect that many of the people who should know better are of this persuasion, and fail to see past it.

I know we all know that PACE and similar trials illustrate the fallibility of combining unblinded trials with subjective outcomes, but it seems there are many people who simply cannot find the insight to realise that. What would be good is if there are other clinical trials, of any kind, that have committed the same blunder, but everyone readily accepts and understands that. An example that is already well accepted, to then try and help convince the doubters - because convince them we must.

 

Is there any other mechanism that could be more effective. A thought that comes to mind is if someone like yourself could run some kind of seminar that MPs could attend. But counter to that is that presumably the BPS crew could do the same thing and confuse them all over again.

 

I remember Amolak Bansal telling me that one of the antivirals had been tried in an unblinded trial in ME and seemed to do wonders, only for a subsequent blinded to trial to show no difference. Maybe valgancyclovir or something?

 

Yes, there is a norwegian one, from 2012 - http://www.me-foreningen.info/2016/05/19/me-pasienters-opplevelse-av-ulike-behandlingstilbud/

You've got a good memory!

green = better, blue = no change, yellow = worse, red = much worse

gradert treningsterapi = get
kondisjonstrening/progressiv fysioterap = fitness traing/progressiv physiotheraphy

But the numbers are a bit misleading, I think, as the 'competence sevice' and thus norwegian physiotherapist, are promoting GET as something that would translate more to "adapted re-conditiong therapy", and really is not the same thing - even if they use pace etc. as documentation. There is less focus on pushing throug set-backs/sympthoms, and used more as a description of doing super carefull re-conditioning. (Still not working though.) I suspect the progressive physiotheraphy would be more like get.

 

A different way of raising the same issues might be to highlight just how few ME/CFS research projects the MRC has funded over the last 15 years. As Steve Brine said in the Parliamentary debate last week,the MRC has had a highlight notice in place for ME/CFS research since 2003 - and yet according to the MRC's own records they've only funded 12 projects since 2004, totalling £6.7 million in awards. Given the size of their research budget (£755.5 million in 2016/7 and £814.1 million in 2017/8 according to their website) £6.7 million over 15 years doesn't give the impression that the MRC really considers ME to be "an area of very high strategic importance" as Steve Brine claimed. Their total spending on ME/CFS research over the last decade and a half doesn't even add up to one percent of last year's research budget.

Two important questions follow from this. Firstly why is it that so few biomedical research applications have been successful? If it's true that (as Steve Brine said) the proposals received have not been good enough, then why on Earth is the MRC not doing more to promote better applications? For example why hasn't the 2011 'call for proposals' initiative been repeated? Why not ring fence £1.5 million (less than 0.25% of the MRC's 2017/8 budget) specifically for ME research every year?

The second question is why poor quality BPS research proposals - I'm talking about FINE and PACE - didn't seem to experience the same difficulties in getting approved, despite the fact that they were applying for substantially larger sums of money (over half of the total £6.7 million that the MRC has spent on ME/CFS research - around £3.6 million - was wasted on FINE and PACE) than other applications. When coupled with the MRC's decision to continue publicly defending the PACE trial despite the widespread criticism from the scientific and academic community, it's understandable why people might start to wonder whether the MRC is somehow biased in favour of research with a BPS slant...

Actually I'm not sure this is entirely true. Sure - the committee would struggle to prove beyond all doubt that the MRC's funding mechanisms were biased, but then I'm not sure they would actually need to. Simply making the allegation might well be enough to get a positive response. Back in 2003 the Science and Technology Committee published a scathing report on the work of the MRC, including allegations of bias in how funding applications were treated. To quote from the report's conclusion:

...there is significant disquiet about the policies and performance of the MRC from individual researchers and organisations. We
realise that we were unlikely to receive submissions from people with no grievances but we have concluded that those who have submitted evidence have legitimate concerns. We have found evidence of poor financial management and poor planning, with too many funds committed over long periods leading to large numbers of top quality grant proposals being turned down. The MRC has introduced misguided strategies for its research support that have discriminated against young researchers and some disciplines.​

Obviously the situation isn't exactly the same - back in 2003 the MRC's problems seem to have arisen from a lack of direction and poor financial planning. But this criticism from the Science and Technology Committee seems to have had a pretty dramatic impact on the MRC, because by 2006 the Chair of the same committee was praising the organisation for it's "clarity of vision and focus".

Isn't it possible that some public critiicism from the members of the Science and Technology Committee might be enough to shock the MRC into getting their act together again? There's only one way to find out.

 

I do appreciate people's frustration but I think it is important to realise that the situation is not as puzzling as it might seem.

In simple terms there are three sorts of grant application. The first is like PACE and is easy to fund. It says that we have developed a treatment that in preliminary studies looks as if it might work and we want to do a large definitive study. It is true that PACE had serious design flaws but that might not have been obvious from the original application, which included objective outcome measures. There is also an odd anomaly that drug studies do not get funded by MRC because industry is expected to invest in them. Studies of procedures like CBT or bone marrow transplantation do get funded because nobody else will. To reject the PACE application you would need to argue that the theory behind it must be wrong. But that is not a scientific approach. The scientific approach is to say, well let's test it and see.

The second sort of application is what PWME want - an application to investigate a theory of whatever the mysterious cause of ME is. So the application might say we have suddenly had this brilliant idea of how we can discover that and we want 10M pounds. The reasonable reaction to this from the MRC, and almost all funding bodies is to ask for some preliminary evidence that this is likely to get anywhere. Alternatively they may set up ring-fenced seed funds for small initial projects. They did that in 2012 and presumably none of those projects has led to anything that looks worth further investment. I did not see anything very exciting at the 2014 Bristol meeting.

The third sort of grant says that we all realise that nobody has a strong enough lead to pursue so let's set up a massive fishing trip to see if we can trawl up some clues. That was the basis of MEGA. MEGA was not well thought out but something much more solid is being thought through just now. One can ask why this sort of approach was not set up ten years ago. I think that is a good question but genomics and metabolomics were not as streamlined in those days. In fishing terms the nets were not big enough to be expected to do the job.

I think people may not appreciate that an organisation like MRC cannot magically increase the rate of good applications of type 2. It is a bit like putting out a call saying 'We invite applications for solving of Fermat's Last Theorem. Applicants must demonstrate that they have identified the method for solving the theorem.' This is of course absurd because if you have identified the method you have solved it.

Biomedical research into causes of disease is like that. Someone has to suddenly have a brilliant idea. It is worth remembering that despite vast amounts of money being poured into research in the last twenty years the output of breakthroughs in understanding how disease work has dropped like a stone compared to the 1980s and 1990s. Even the development of novel treatments has petered out for most conditions.

I realise that people may think that there are lot of brilliant leads being developed in the USA on NK cells, viruses, cytokine profiles, metabolic traps, and so on. But the sad reality is that the original data are not very convincing and replication studies have tended to show nothing. Moreover, it is doubtful that the theories that have been put up make much more sense than the psychological ones. Moreover, replication needs to be done by people who are genuinely expert in the technologies involved. Neuroimaging studies need to be replicated by people who understand neuroimaging in great detail. The CureME team in London had an NIH grant to replicate NK findings because they were experts in NK cell biology. Nothing was found.

I don't want to seem pessimistic. I am actually very optimistic that finally the science community is taking ME seriously. The MRC know full well that people think they have let them down. We do not need a Parliamentary Committee to tell Fiona Watt what she knows all about. She has sat round a dinner table with Steven Holgate, Dan Peterson, Maureen Hanson, Don Staines, Charles Shepherd, Luis Nacul and everyone else and listened to the story.

But I think it is worth realising that the situation has been bad not so much because of political interference, although there has been that, but just because human beings are not always quite as bright as we take them to be. Money does not buy bright ideas. In the golden age of biomedical science (1970-1990) ME was too difficult a problem to tackle - nobody could find anything. Now is the time to try, but before you can make sensible use of money you need intelligent dialogue between clinicians and scientists of the highest calibre about where the likely answer lies. I see that happening now but it is going on in quite corners.

 

Jonathan - thanks for taking the time to provide such a detailed breakdown of where we are with regard to the current research landscape.

Although I don't have a science background I tend to agree with your analysis that there probably isn't a great deal of research that the MRC could and should have been funding over the last 15 years. The point I was trying to get at in my last post - and I should have been clearer about this but it was late and I was tired - was that the MRC has certainly seemed from the outside to 'buy in' to the BPS hypothesis over the last couple of decades. They made sizeable awards to contentious BPS research proposals, didn't adequately perform their oversight functions when the PACE methodology was changed mid-trial and they have carried on defending the published results long after many respected figures in the scientific community have highlighted the problems. Whatever the justifications for these actions - and the MRC may well have what they consider to be perfectly good justifications - one of the consequences (perhaps unintentional) has been that the MRC has acted as a supporter and enabler (perhaps inadvertently) of the BPS brigade.

Putting the science aside for a minute - which I appreciate is not your preferred way of approaching this - from a political point of view now might be the perfect time to apply a bit of pressure to the MRC, with the express intention of making them squirm a bit and look again at how they've been handling ME research. Not because there's been a long list of good quality research proposals that they should have funded (I accept that there probably isn't) but because they need to consider what unconscious biases they may have developed as an institution in this research area, and also to acknowledge their past failings (with regard to PACE and FINE) that have created doubts in the minds of patients about their impartiality.

Last week's parliamentary debate - in which no-one (apart from the Health Minister, who didn't really have a choice) spoke in support of the MRC's record on ME/CFS research shows how much the debate has changed in the last couple of years. If members of Parliament's Science and Technology Committee are willing to start publicly asking some critical questions of the MRC's record, I think that's something we should encourage. Not because the MRC has a lot to be sorry about - but because it might provoke a change of attitude and approach that would be helpful going forward. As you say, Fiona Watt may well know that people feel the MRC has let them down - but it doesn't seem to have sunk in that writing letters to The Times giving PACE a clean bill of health isn't going to help matters. A bit of scrutiny and some pointed questions from Parliamentarians might well help change that.

 

Whilst technology is developing certainly I would not accept that ME more than other illness, was totally unresearchable in the past. Especially on severe ME, the tiny Newcastle study showed that with that community they really hadn’t done anything in the past - they didn’t know the numbers, who they were in their area because the service I don’t think did Severe ME care, certainly not at a physician level, just basic questionnaire stuff hadn’t been attempted before. Bandai had wanted to have an inpatient centre where he could care and research the severe, no funds. So we were 2016 and the first uk feasibility study into severe ME was done. PET scans could have been done many years ago , and you might think they would have given the name. Dr Charles Shepherd had some Biopsy stuff done on his muscles which showed something afaik he couldn’t get It replicated.

I think that the current attitude and behaviour of the MRC , totally detatched from the patient community, blaming US for the research disinterest, well fastened to the BPS approach and its research, very supportive of people like Wessely and wanting people like white and Crawley in there, highly reluctant STILL to put in money to incentivise research is how they have been all along. If the reason the MRC was holding off really was research leads etc then when things really heated up they would have sprung into action like the NIH, well kinda sprung with a few more coins. And Ring fenced funding ten years ago wouldn’t have equalled throwing £10m to some crazy bidder.

 

I agree entirely. Surely the MRC When being informed of a major health problem not progressing should do more than say c’est la vie, there’s no interest, there’s no leads. It’s not all MRC fault, medical education and medical literature out there is either putting off Drs or failing to inform them in a way that might excite interest, and MRC know there’s barriers to getting interest. But just shrugs from all quarters Is what we have had for decades and i think that eventually When this is all looked at it will be regarded as a sorry failure.

 

Yes, I think we are actually arguing for the same thing. I have been trying to discourage people from pressing to set up an enquiry that hopes to show that the MRC has been 'biased', using numbers of grant applications or whatever. What I argued a few posts back is that it would be reasonable to have a formal enquiry into the poor handling of PACE, but that since these committees like a wider remit that ought to be extended to the whole empire of IAPT, MUS, liaison psychiatry and soft psychology trials. That would be justified but it is a big undertaking and not even Carol Monaghan may have the stomach for it.

I think there is a distinction between buying in to a hypothesis and buying in to a shoddy programme. I do not see that we can argue that the MRC was wrong to try to test the BPS hypothesis. If it was right and CBT led to recovery everyone would be happy. I think what you are meaning is that they bought in to a continuing programme of research that could be seen to be valueless pretty early on. I am not quite sure how early on that was. If the original PACE trial included actometry and a realistic definition of recovery then at that stage it might not have been too bad - with an objective outcome measure. The real problem has been the incompetence of the internal 'experts' supposed to keep tabs on what happened subsequently.

Fiona Watt knows that a number of intelligent academics are questioning PACE. She has chosen to stick with her advisors and defend it. So there must still be advisors in there who defend PACE. What is not clear to me what 'in there' means. Maybe it is colleagues at dinner at the Royal Society, not actually part of the MRC structure itself. Once you get into this are 'MRC' ceases to be a definable entity. There is a network of people who convince each other they know what's what. there are, no doubt, others within MRC who take a different view, which is why we seem to be getting some progress, but they are presumably not at the highest level.

As you know, I took the opportunity personally to invite Watt to reconsider her view on PACE, presenting her with the simple key arguments. She ignored them and stuck to her position. My feeling is that further attempts to get her to admit an error will only sour things. It would be much better to allow the MRC to get on with inviting funding proposals, as it is now, and forget predecessors mistakes, at least until they are dead and buried.

And the problem is not really the MRC. I think people have got too focused on MRC. NIHR has a much greater responsibility to get practical clinical research right. NICE has a responsibility to get assessment of evidence right. Universities have a responsibility for the quality of work on site, and so on. If there were to be an enquiry into the problems of trials like PACE then I think it should be an enquiry into the programme, not any specific funder.

 

But how do you encourage better proposals? Do you say to Einstein when he sends in Special Relativity that you want something more General? Science cannot work backwards from breakthrough to proposal. How do you encourage interest? No doubt there are ways but be careful what you ask for. If they had set up a centre of excellence and advertised for a chair in ME research with a 2M pa budget then who would have applied. No doubt Esther Crawley or Carmine Pariente. And no, you cannot turn an applicant down on the basis that 'we think you do the wrong sort of research'. In science everything is treated as something to test.

Which brings us back to that other point - that one of the main reasons I think early criticism of PACE failed is that it was all about 'this is the wrong sort of theory'. 'We don't like psychology'. What should have been said is that this proposal is incapable of testing the theory it is supposed to test. And even that might be wrong because PACE probably did do what you are supposed to do in science - it refuted the theory rather nicely. A more optimistic attitude (at least as reported) did not produce reduced disability.

 

Dialogue like a description of how the illness affects patients in every day situations?

I came back from a visit from the hospital and now would be a good moment to describe how I react to such an exertion. I walked to the hospital and back. I felt increasingly uncomfortable and lightheaded at times. After arriving at the hospital, I sat down. Very soon afterwards, I felt exhausted. When it was my turn, I stood up and felt weaker. My walking speed also decreased. While with the doctor, it felt like I had to make an effort to pay attention, listen. I did not speak much. While walking back home, the weakness decreased and walking speed increased as the body adjusted to the exertion. However the lightheadedness and discomfort continued to gradually increase. As soon as I arrived at home and slowed down, the exhaustion and weakness increased sharply and were more intense than before. I ate something and sat down and checked the forums. After a while, perhaps half an hour I felt increasingly cold and sleepy and went to bed to warm up and rest with eyes closed. I wanted to continue but also felt the urge to write this, hoping that it will be useful information. The visit to the hospital was just to put on a blood pressure monitor. Now I'm going to lie down and rest a bit.

 

It’s interesting that you use the example of Fermat. One of the reasons that Fermat’s Last Theorem held such fascination for mathematicians for so long was because Paul Wolfskehl bequeathed the equivalent of $2million in his will to anyone who could solve it. The Wolfskehl Prize was eventually awarded to Andrew Wiles.

Similarly, in mathematics there are the Millennium Prize Problems, each with a $1million reward, and before that there were the Hilbert Problems. The point of these prizes is that they publicise the importance of the problems to the mathematics community – they generate interest from best mathematical minds.

By contrast, most people who might have the capability to crack the ME problem have been positively deterred from getting involved by the false narratives that have been spun. They have been told that 1) there is almost certainly no abnormal pathology to find 2) ME can be reversed by patients own efforts, and 3) that working in ME research is fraught with danger because the patients are so unpleasant.

The DHSC, MRC and the NIHR may not have been responsible for inventing these false narratives but, at the very least, they have failed to correct them or to do anything to counter the damaging effects they have had on attracting interest from biomedical researchers.

My feeling is that ring-fencing a large sum of money for high-quality ME research would do for ME what the Wolfskehl Prize did for Fermat’s Last Theorem, and what the Millenium Prize did for the Poincare Conjecture. It would generate interest from the best medical/scientific minds by signalling that this is an important problem that needs to be solved, and that funding will not be an inhibiting factor for high-quality research in this field.

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Meanwhile, it seems that there is some agreement that it might be wise to push for a broad Parliamentary inquiry into PACE, ME, MUS, IAPT, standards of research in psychological medicine/psychiatry etc. as a next step. Would it be wise to start a new thread on this and invite the various ME charities, organisations and other advocates to engage with it?