UK Research Collaborative Conference in Newcastle: 13th - 14th October

[Dolphin]

I know it's distressing for those involved but my understanding is that the cost-benefit issues tend to be related to very expensive drugs that have borderline or minimal benefits. The NHS does provide plenty of expensive drugs. If rituximab helps half to two-thirds of patients then I can't imagine it being refused on cost grounds.

Cheaper treatments than Rituximab can be ruled as not cost effective.

The PACE Trial cost effectiveness paper (McCrone et al., 2012) gives an idea how such decisions are made:
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040808

If one can get a better idea who a treatment will work for, it helps making the cost effectiveness argument.

 

[MeSci]

I agree; I still do not see how this is supposed to work in the framework of Bayesian 'forward models' of perception. You should get the opposite effect. Moreover, my limited experience of post-EBV fatigue (6 months) was the opposite. There remain two distinct memories from 50 years ago fresh in my mind. The first was sweating and feeling sick after a minor attempt to go canoeing around 6 months after EB infection. I said to my mother how miserable I felt that I could not go out on the water with the others. She explained to me (she was an EB virologist) that this was common for about 6 months after being ill. The second memory is of being out in the open about two to three months later and running and suddenly thinking 'wow, I can do this; nothing is stopping me any more'. So the theory fails. When the bad input fails to arrive the response is not the same old misery but the opposite - an exaggerated feeling of wellness, enough to remember for a lifetime. That is what the Bayesian forward model should give you, just as you see the other train as going backwards when in fact it is your train that has started going forwards too slowly for you to feel.

Maybe the theory would say that my brain unlearned the bad expectations that had lingered on for 6 months. But I didn't do any graded exercise therapy. I just went out one day and found the malaise was gone. How would the theory deal with good patches and crashes in ME? i cannot get my head around it.

Same here. When I have a good day, I feel good and pleased about it, sometimes elated! When I can do more than usual, I do more than usual, and revel in the fact that I don't suffer for it. When a particular treatment seems to be bringing about significant improvement, I get excited, hoping that I might be on the road to recovery - even after 20 years. After many setbacks, I am more cautious, but the optimism is still there. The nearest I get to the pessimistic approach that Mark Edwards and others seem to attribute to us is taking PEM and my past experiences into account when planning my activities. It's based on common sense - again, an evolutionary trait that favours survival and safety. No 'catastrophising'. I am offended by that assumption.

 

[Snow Leopard]

I know it's distressing for those involved but my understanding is that the cost-benefit issues tend to be related to very expensive drugs that have borderline or minimal benefits. The NHS does provide plenty of expensive drugs. If rituximab helps half to two-thirds of patients then I can't imagine it being refused on cost grounds.

If the (current) Rituximab trials demonstrate efficacy, then there is going to be a shit-storm when patients start demanding approval and treatment, while government agencies are slow off the mark...

 

[Snow Leopard]

The ME/CFS Biobank aims to open for the supply of samples to research groups in early 2016.

Fees, which are currently being calculated, will be based on cost recovery only.

Just curious, but is access also available to overseas researchers and what is the ballpark for access costs? (not necessarily the whole group, but say 20 patients/20 controls, blinded samples for a pilot study)

 

[Woolie]

If mind is effect and brain is physical then don't we need some way of saying what mental processes are automatic or where thoughts are not explicit but that could be said to have an overall affect on cognition. For example, language processing is pretty automatic yet infringes on conscious thought - I was particularly thinking of the conversion from sentence structure into an internal mental representation but has an impact on what we understand others saying.

Hey good question. I think you just said it, a very small proportion of mental processes are available to conscious awareness. Most aren't. I see mental processing is like a huge iceberg, with the "tip" being processes we are phenomenologically aware of. Even most sentence comprehension happens automatically, without our awareness.

There's a frontal-posterior element to it: mental processes which engage posterior cortex usually don't impinge on awareness, whereas effortful ones supported by prefrontal cortex sometimes do. But then many of our decision making proceses, despite being supported by prefrontal cortex, seem not to be available to awareness.

You've got this inner speech, which is like our cognitive "narrator", but its debatable as to how accurate it is (probably not very).

I agree, we need both levels of description, and we need to keep the distinction clear in our heads. People tend to be seduced by "brain talk", and can think if a brain part is involved suddenly a psychological explanation is better, more satisfying. Have you seen this:

The seductive allure of neuroscience explanations
Advanced psyc students were asked to read explanations of a psychological study. Some of explanations threw in a "brain part", which had nothing to do with the explanation, just said what part of the brain might be involved (not how it was involved). The students rated the explanations with the brain bits as being more satisfying.

This is all interesting stuff, but there's a real reason for my worry: the psychobabblers are now onto this. Just cos something mentions "the brain" does not mean it isn't the same old psychological stuff repackaged, with CBT as its recommended treatment. For this reason, we should be very wary of the interoceptive network. I didn't say before, cos I wanted to hear what others think, but I suspect the outcome of such work in MECFS is very likely to be a recommendation of CBT or maybe antidepressants.

I guess I would argue that it is not sufficient to talk of mind or brain but proposals should be made in terms of specific neurological things or mental processes.

You should be able to explain the phenomenon at either level of description. That's the test of whether you're clear about what the brain-level stuff adds (sometimes, nothing, just a location in the brain where these mental processes might happen. But sometimes - just sometimes - it adds new insight).

 

[Sidereal]

This is all interesting stuff, but there's a real reason for my worry: the psychobabblers are now onto this. Just cos something mentions "the brain" does not mean it isn't the same old psychological stuff repackaged, with CBT as its recommended treatment. For this reason, we should be very wary of the interoceptive network. I didn't say before, cos I wanted to hear what others think, but I suspect the outcome of such work in MECFS is very likely to be a recommendation of CBT or maybe antidepressants.

This is exactly what I suspect is happening. In 2015 we are supposed to be rejoicing that a psychiatrist and a neurologist who studies hysteria are revisiting the same old psychobabble concepts of the early 1990s now repackaged in neurobabble language. Ultimately when it comes to this disease it always boils down any identified "brain loop" leading to a prescription for CBT, GET and antidepressants. Studies have been showing inflammation and activation of this network in depression for years/decades but this has not led them to modify their treatment recommendations for depression, it's the same old crap. It's not going to be any different for ME.

 

[Woolie]

agree it's important not to offend patients, but I've got a problem with the "what's less offensive to patients" stance. It's what Stone et al. were trying to achieve in the paper about the numbers needed to offend (a nice way to say a "truth" disturbing to patients).

I'm with you 100% here, @Cheshire. I think the brain-based explanations have the danger of hoodwinking us, just as these docs hoodwink their patients.

At first glance, the brain ideas sound new and different from the usual psychological claptrap. But they might very well turn out exactly the same, just packaged in new terminology. @Sidereal is very wise to this, and has been commenting on the danger for a while

I think we patients should be very, very skeptical about any research that involves brain neuroimaging. I personally think that despite the cognitive features of MECFS, the brain is NOT where we should be looking for causal explanations.

Plus, the simplest, most elegant explanation for immune-type problems is a disturbance of the immune system. Building some elaborate edifice about brain-centered symptom misintepretation and modification - no matter how "brainy" it sounds - adds a layer of complexity that is not justified at present.

 

[A.B.]

At first glance, the brain ideas sound new and different from the usual psychological claptrap. But they might very well turn out exactly the same, just packaged in new terminology. @Sidereal is very wise to this, and has been commenting on the danger for a while

Susan Sontag’s dictum: Theories that diseases are caused by mental state and can be cured by willpower are always an index of how much is not understood about the physical basis of the disease.

 

[charles shepherd]

If the (current) Rituximab trials demonstrate efficacy, then there is going to be a shit-storm when patients start demanding approval and treatment, while government agencies are slow off the mark...

The economic cost to the country (UK) of ME/CFS in terms of lost taxes, DWP benefits, health costs etc is enormous - and has previously been estimated at around £3 billion

Which is why I don't think there would be any quibble from NICE when it comes to funding a licensed treatment for ME/CFS if it can be shown to be safe, of significant benefit (and in which sub-group of patients) and that this benefit/even recovery can be maintained for a significant period of time - in other words people returning to work and coming off benefits

But evidence from a few small trials from overseas (as is currently the case with valgancicolovir) and clinician evidence just isn't good enough for NICE

Neither will the results from just one phase 3 trial of Rituximab, currently taking place in Norway, where we will have the results in late 2017 or early 2018

Which is why we need some large independent RCTs involving Rituximab outside Norway, as well as some further assessment of valganciclovir, as was discussed after Jose Montoya's presentation

Incidentally, one of the poster presentations at Newcastle covered the cinical trial of Rituximab in primary biliary cirrhosis:

https://clinicaltrials.gov/ct2/show/NCT02376335

a condition which has some interesting overlaps with ME/CFS, that is now taking place in Newcastle

PBC trial:

Primary Biliary Cirrhosis (PBC) is a liver disease that predominantly affects females, can present for the first time at any age and which develops over many years. It is caused by the immune system attacking the body's own tissues. People with PBC frequently experience profound fatigue or tiredness which they liken to their "batteries running down" and although people still want to undertake normal activities they often lack the energy to be able to do them. This reduces quality of life, makes it difficult for people to work and can end up with them becoming isolated in the community. At present the investigators have no treatment for fatigue in PBC. Finding a treatment for fatigue in PBC is one of the highest research priorities identified by patient groups.

The aim of this study is to undertake a clinical trial to examine the effects of a treatment ("Rituximab") on severe fatigue in PBC to help us understand whether this will be a potentially useful treatment. The information that this will give us about how energy generation changes in patients with PBC with and without the treatment will also help us to develop new treatments for fatigue in other diseases. The study has the potential to improve the quality of life of many patients with PBC, for whom there is currently no hope of improvement.

The investigators will perform a randomised controlled study of Rituximab therapy in PBC compared to placebo (1:1 ratio).

The study will be performed in a specialised clinical research environment at Clinical Research Facility Royal Victoria Infirmary. The investigators have, for many years, worked closely with PBC patient groups to focus on the problems that are important to our patients. This study is fully supported by Liver North, a liver disease charity and patient support group.

The study will take place over one year and will involve between 9 and 20 visits although a number of these will be telephone visits. Blood tests and quality of life questionnaires will be performed at the start of the study and after three, six, nine and twelve months. At baseline and 12 weeks follow up physical activity will be monitored using monitors, and an exercise test and MRI scan will be performed.

 

[charles shepherd]

Just curious, but is access also available to overseas researchers and what is the ballpark for access costs? (not necessarily the whole group, but say 20 patients/20 controls, blinded samples for a pilot study)

We are intending to make samples available to overseas research groups and have already had some interest from two overseas groups

I don't want to give any figures at this point because the Steering Group is still in the process of discussing a paper on costings which takes into account the basic cost of running the biobank and the cost of replacing samples as they are used

We are not in the business of making a profit but will, like any other biobank, have top cover our costs

 

[Snowdrop]

Re: choosing rituximab over CBT

We also have a tendency to fall into the trap of the rational actor. As if researchers and people who make decisions as to wether to allow a drug for use or to have it covered by insurance is really a decision based on listening to good data or choosing what a rational actor would choose.

These are political decisions and what you or I see as the appropriate course of action may not be the one chosen by those who have the power to do so.

 

[Snow Leopard]

Neither will the results from just one phase 3 trial of Rituximab, currently taking place in Norway, where we will have the results in late 2017 or early 2018

The requirement for large sample sizes in phase 3 trials is not necessarily to demonstrate efficacy, it is to demonstrate safety. The most efficacious drug is not so great if it kills one in two hundred people and you need decent sample sizes to show with some statistical confidence that it doesn't. We don't have that problem as the safety can be proven with other Rituximab trial data.

Smaller studies can demonstrate efficacy if the effect size is strong enough. The evidence on efficacy presented to government departments would be a meta-analysis of the 3 double blinded trials (up to that point).

 

[charles shepherd]

The requirement for large sample sizes in phase 3 trials is not necessarily to demonstrate efficacy, it is to demonstrate safety. The most efficacious drug is not so great if it kills one in two hundred people and you need decent sample sizes to show with some statistical confidence that it doesn't. We don't have that problem as the safety can be proven with other Rituximab trial data.

Smaller studies can demonstrate efficacy if the effect size is strong enough. The evidence on efficacy presented to government departments would be a meta-analysis of the 3 double blinded trials (up to that point).

That's a perfectly valid point about safety

And from what we know so far, Rituximab has a good safety record in ME/CFS patients - Oystein Fluge updated us with some data on adverse reactions at the RC conference

But the numbers are still fairly small and this is a drug that has a potential to cause serious adverse reactions. There are also questions over longer term use and safety. So this is an aspect that ethical committees and the regulatory authorities are going to be very interested in.

And from the point of view of efficacy, I think that we would need at least three large RCTs demonstrating safety and significant efficacy in order to make an expensive drug such as this available on the NHS here in the UK

The situation may be rather different in Norway…..

 

[Jonathan Edwards]

Which is why I don't think there would be any quibble from NICE when it comes to funding a licensed treatment for ME/CFS if it can be shown to be safe, of significant benefit (and in which sub-group of patients) and that this benefit/even recovery can be maintained for a significant period of time - in other words people returning to work and coming off benefits

But evidence from a few small trials from overseas (as is currently the case with valgancicolovir) and clinician evidence just isn't good enough for NICE

Neither will the results from just one phase 3 trial of Rituximab, currently taking place in Norway, where we will have the results in late 2017 or early 2018.

I agree with the general drift of your comments, Charles, and certainly agree that more rituximab studies in ME would be worthwhile. I might say, though, that NICE is probably too unpredictable to second guess either way. They very nearly withdrew approval for all biologic treatments for RA. Because most severe cases are now on biologics and mild cases on methotrexate they did a study that found that people tended to be just as good on methotrexate so decided to axe biologics. Fortunately, I think the message got through that their health economists did not know their hawks from their elbows. And there are examples of drugs getting approval without the usual raft of RCTs. I don't think we can predict, but common sense does seem to win out after a struggle. More trials can only be a good idea though. There is an awful lot more we need to know.

 

[Jonathan Edwards]

Incidentally, one of the poster presentations at Newcastle covered the cinical trial of Rituximab in primary biliary cirrhosis:

The aim of this study is to undertake a clinical trial to examine the effects of a treatment ("Rituximab") on severe fatigue in PBC to help us understand whether this will be a potentially useful treatment. The information that this will give us about how energy generation changes in patients with PBC with and without the treatment will also help us to develop new treatments for fatigue in other diseases. The study has the potential to improve the quality of life of many patients with PBC, for whom there is currently no hope of improvement.

I continue to be a bit puzzled about the relevance of this study to ME. If rituximab improves fatigue in PBC it will be because PBC is a B cell driven disease and rituximab removes B cells. I am all in favour of doing the trial but I do not see how it tells us anything special about fatigue, which will be mediated downstream. Moreover, it seems unlikely that fatigue is mediated the same way in all the different diseases it occurs in - TB, flu, heart failure, cancer, MS, marathon running. Fatigue occurs in rheumatoid arthritis and improves both with TNF inhibitors and rituximab. One could easily study improvement in fatigue in a large group of rheumatoid patients on TNF inhibitors. This looks like a good trial for people with PBC but it will not add to the evidence for rituximab being useful in ME.

 

[Jonathan Edwards]

For this reason, we should be very wary of the interoceptive network.

I think the wariness about this jargon is well founded, but it would be a pity to close the door to good research just on that basis. Interoception is just sensing the state of ones body rather than the outside world. Cramp in the calf is interoception. Feeling ill with 'flu' is interoception. In RA we began to crack the problem when we discovered that a particular mediator of interoception, TNF, was involved. That led us on to realise what B cells were doing (making antibodies that trigger the TNF). So the immune system is interoception. The big question is really whether the immune part or the neurological part of interoception is causing trouble. I realise that many psychologists and psychiatrists use interoception in a narrow sense but people like Neil Harrison do not. He is as much interested in cytokines as brain areas.

Moreover, even if the problem is immune, since we cannot find the peripheral signals it would be hugely useful to find an objective measure of what those signals are doing to generate symptoms in the brain. We came to understand the way paracetamol and aspirin help fever by discovering that there is a temperature control centre in the hypothalamus that these drugs act on. In ME we need to work out what any hidden peripheral mediators are doing to the brain and where - we need to understand the interoception involved. Since we cannot find the mediators peripherally it makes sense to look at where they might be acting I think.

 

[Woolie]

I hope you're right, @Jonathan Edwards!

This is promising:

http://sro.sussex.ac.uk/7047/1/Neil...eroceptive_Responses_to_Inflammation_2009.pdf

But I notice nothing correlated with levels of IL-6, so the proposed link between inflammation and engagement of the interoceptive network is a bit indirect. Bit of a worry, as PWMEs will not have the benefit of being classed into groups of vaccinated vs. unvaccinated, so everything will have to depend upon actual cytokine levels (or indirect inference based on whether they just exerted themselves or not).

You're not at all concerned that the interoceptive network is viewed as the origin of many of the "somatic" complaints that accompany states of psychological distress? And as the initiator of a cycle that includes increased levels of cytokines in these conditions? (IL-6 is big in these models, I believe?)

 

[BurnA]

And from the point of view of efficacy, I think that we would need at least three large RCTs demonstrating safety and significant efficacy in order to make an expensive drug such as this available on the NHS here in the UK

The situation may be rather different in Norway…..

I don't see why 3 are required. Mathematically or logically what do three rcts tell us over one rct?
It might give us finer response rate and marginal improved accuracy in safety data but from an approval perspective these should not be required initially. If safety is understood and efficacy is shown approval should follow. Additional data can follow if required.

If 3 are required in this case why not in all cases?Does it mean the results from one rct are untrustworthy - if so what does that say ?

I think we should stick to logic and not spread ideas that could be picked up on, regardless of what the thinking may be. What I mean is we should all expect it to be approved based on 1 rct and be shocked if not, rather than expect it not to be approved because of no logical reason.

But of course if there are logical reasons why 3 might be required pls let me know.

 

[charles shepherd]

I don't see why 3 are required. Mathematically or logically what do three rcts tell us over one rct?
It might give us finer response rate and marginal improved accuracy in safety data but from an approval perspective these should not be required initially. If safety is understood and efficacy is shown approval should follow. Additional data can follow if required.

If 3 are required in this case why not in all cases?Does it mean the results from one rct are untrustworthy - if so what does that say ?

I think we should stick to logic and not spread ideas that could be picked up on, regardless of what the thinking may be. What I mean is we should all expect it to be approved based on 1 rct and be shocked if not, rather than expect it not to be approved because of no logical reason.

But of course if there are logical reasons why 3 might be required pls let me know.

Would you apply the same logic to the value of just one RCT if this was applied to CBT or GET, or any other form of behavioural or psychologically based treatment in ME/CFS ? !

 

[BurnA]

Would you apply the same logic to the value of just one RCT if this was applied to CBT or GET, or any other form of behavioural or psychologically based treatment in ME/CFS ? !

Haha I take your point but the weakness in any cbt / get trial is in the design not the number of trials.

I guess what I am saying is if 1 phase 3 trial suffices for drug approval in most cases we should expect the same logic to be applied.