The P2P Draft report is out

[Bob]

I have to say that I am completly lost from this P2P. I tried to read this thread, I saw some advocate´s/ patient´s statements but they are so contradictory. I have impression that we are not able to find any agreement in our community. What positive brought us this year regarding ME? Governements dont listen us, patient´s advocates are arguing, we dont have money for ME research. Patients are completly lost and dont understand what´s good anymore. The situation doesnt look optimistic at all but maybe in 100 years it will be different. Pity that we will not be here.

I know that many of us are really struggling with this illness, on a day-to-day basis, and desperately need answers and treatments now. But (ignoring governments for a moment) I really believe that there are more reasons to be optimist now, than any time in the past 30 years. We now have some major scientific names getting involved in ME research for the right reasons. And we also have some major charitable foundations, and private individuals, giving massive amounts of money.

There are so many major research projects going on, that I can't keep track of them. And there is an increasing number of major scientific players getting involved in the field.

There are various researchers at Stanford Uni doing various large-scale projects; various major ongoing projects in Australia; IiME's research projects in the UK; Fluge and Mella in Norway; Julia Newton in the UK; Lipkin & Hornig at Columbia Uni; various major CFI projects; the solve-CFS (CAA) pilot studies; the major biobanks in USA & UK; Simmaron Research; the OMF projects; the End ME/CFS project; and Ron Davis at Stanford embarking on a major new journey into ME/CFS.

All of these projects involve major players, many new to the field. And these are just the ones I can think of off the top of my head. There are even more ongoing large research projects but I can't remember the details. And there are major charitable foundations (some of which I can't remember the name of) that have been funding large projects. The CFI, and the Edward Evan's foundation are a couple, but I've come across another foundation recently that has been funding useful ME/CFS research. And I think Montoya received a $5m donation from a private individual. And we've had some successful crowdfunding projects.

So I think we have reasons to be optimistic that we will see some treatments and serious research findings emerging in the foreseeable future. Never soon enough, but at least in the pipeline.

 

[Bob]

I hope that people will actually write in with their comments. I'll certainly be doing that.

Even if it's only one or two lines saying what we like or don't like, I think it will be helpful.

For example, if they get a large number of comments saying that it's unhelpful to say that ME overlaps with major depression, or saying that there's no evidence that CBT changes objectively measured outcomes (e.g. physical disability), then perhaps they will take notice.

 

[Jonathan Edwards]

@Jonathan Edwards - You have stated that in all your years being a clinician and in research, the criteria never mattered. I can't argue with you because I respect you as an excellent clinician and researcher in your field. I just have a question for you. When you were researching the treatment of Rituximab for RA, What if 1/4 of your patients actually suffered from Fibromyalgia and another 1/4 from Osteoarthritis (both have similarities with RA) How successful would your findings have been?

The problem would not have arisen because I have never believed in 'diseases'. I used to get a lot of stick from my bosses for being difficult and refusing to do so. If someone had persistent pain for which there was no adequate explanation in terms of damaged joints or whatever then for me that is what they had. I never used the term fibromyalgia - partly because my colleagues used it to mean they did not believe the patient's story - it was a code word for 'one of those'. If a patient had a worn out joint, for me that is what they had, not 'osteoarthritis' which again is a term doctors use to pretend they know what is going on when they do not.

So when I treated the RA patients I was interested in the possibility that the inflamed swollen joints that they had, which were associated with a raised CRP and bone dissolution on X-ray was all due to antibodies forming complexes in the joints and might respond to blocking antibody production. They all had the problem I was theorising about. It did not matter whether anybody called it RA.

I realise how important it is for PWME to have their illness recognised but producing some new criteria that are supposed somehow to be the best way to select cases of a hypothetical disease called ME, when it is likely that there are several of them, looks to me to be going in the wrong direction.

I am not at all suggesting using vague criteria for fatigue, except when it would be appropriate to do that. I think criteria for any particular study should be much tighter then any set of criteria used for diagnosis - but tighter in a way that is relevant to that particular study. It will be different in each case. I think the P2P idea that variable criteria has wasted research is wrong. The waste comes from not thinking through the biological questions.

What I would like you to consider is that many of us have been severely sick, living a disabled, painful life for decades. We have felt rejected, neglected and abused by our government health agencies. You are pretty new to the scene of this disease. We have been fighting this for too long. Most of us do not have many years left. We need to see ME be tackled as the serious, distinct disease it is. It is only then that there could be some hope for a better future.

I think you need MEs to be tackled as the six or twelve overlapping diseases they are. That is what the key researchers are all agreeing on now I think. We want criteria so tight they only allow one ME at a time - if that is appropriate to a question.

 

[Denise]

Even if it's only one or two lines saying what we like or don't like, I think it will be helpful.

For example, if they get a large number of comments saying that ME should not be compared to major depression, or that there's no evidence that CBT changes objectively measured physical function, then perhaps they will take notice.

Please submit comments - with references whenever possible.

When you submit comments please note that they ask us to:
" Please reference the corresponding line number of the report.... (https://prevention.nih.gov/programs-events/pathways-to-prevention/workshops/me-cfs/public-comments)

 

[Sing]

I realise how important it is for PWME to have their illness recognised but producing some new criteria that are supposed somehow to be the best way to select cases of a hypothetical disease called ME, when it is likely that there are several of them, looks to me to be going in the wrong direction.

The waste comes from not thinking through the biological questions.

I think you need MEs to be tackled as the six or twelve overlapping diseases they are. That is what the key researchers are all agreeing on now I think. We want criteria so tight they only allow one ME at a time

@Jonathan Edwards Selecting these few statements above from your interesting response, I am reminded of what Dr. Nancy Klimas said in P2P about subgrouping as a means for advancing research. I wonder what the subgroups would be, of course, and wonder if they would be taken up and used by different researchers across the field? Dr. Klimas did not specify the kind of subgroups she has in mind during the P2P meeting but I believe she and other researchers in our field are starting to think this way.

In your view would it make sense to subgroup based on predominant, most difficult symptoms from the patient's perspective, or would it be a particular biological finding, such as a kind of immune overactivation, or immune underperformance, or degree of autonomic dysfunction, or brain scan finding, etc.? How do researchers select subgroups?

 

[Jonathan Edwards]

Having read and thought I find it hard to formulate a response, but here goes. It seems that this was a committee that brought together some experts in ME research and some people with broader healthcare agendas, the latter presumably intended to provide balance and overview. In the event the output reflects the interests of the people involved - rather transparently.

The good news is that the experts include some people who are pushing for exactly the right things. The bad news is that the 'overviewers' seem to have muddied this with politically correct padding and off-target proposals of their own. Goodness knows what the political impact will be but my impression is that we should be pleased that a few very good minds got together to think about strategy and whatever they produced in terms of a report they probably benefited both themselves and the ME community by comparing ideas.

The specific research issues highlighted look sensible to me. Neuroimaging. Immunological assessment. Replication and consensus formation on findings like NK cell function. Population based cohort studies with systematic data and sample collection to assist the above. Continued screening for pathogens. Maybe none of that is so new but it seems a good set of choices.

They also say some sensible things about the difference between statistical significance and clinical significance and significant to the patient. I would like to have seen something a bit sharper edged on that though.

I am sceptical about a stakeholder group producing 'ideal' criteria. As Heapsreal says, money would be better spent on other things.

This group seem to have made a decision to declare their belief that ME 'is not a disease of psychological etiology'. That sounds good but is this actually thought through or is it just a convenient response to 'listening to patients'? That may sound cynical but it would cost them nothing to say this because they know it will go down well. On balance I think they can be taken as meaning what they say. Dr Hornig is a psychiatrist but one definitely interested in the immunological side of brain disease. I would have liked to see more scepticism about CBT and GET but what they do say is actually pretty non-commital (they said people improved rather than 'it works') and they do say that these are not primary treatments.

The fly in the ointment is that the alternative scenario that seems to be offered is in some ways even more worse than the PACE based option. CBT and GET are seen as part of a wider multimodal treatment, including 'self-management' provided by a 'multidisciplinary team'. Where is the trial that even hinted at this approach? What are the unproven modalities recommended. They admit there is no evidence to support 'self-management' strategies but the assumption seems to be that this needs rectifying because these strategies are obviously a good idea.

In my experience 'self-management' and 'multidisciplinary team' are code words for 'pass the buck'. Doctors like them because they can pass the buck. Nurses and physios like them because they feel important if they are allowed to carry the buck they have been passed. Health systems like self management because it sounds cheap, although it is in fact expensive so never works. And as far as I can see what we already have is the real self management - PWME trying to get on with their lives because the multidisciplinarians don't have any skills to offer. Or if they do it is because certain dedicated people have just listened to patients and offered to share the experience with other patients. So this all sounds to me the sort of guff that medical education departments get into rather than just taking time to look after people as best you can.

There is, unfortunately, a definite sense that the people in charge of this group are using it as a piece of mumbo jumbo propaganda of the sort you get in health sciences departments. But maybe that does not matter.

And I cannot quite make out why homeopathy is in their either - other people have had thoughts on that. What I think they should say is that trials should be done on alternative therapies by the people making money out of those therapies- and that they should be obliged to do so just as the conventional people are.

The important thing for me is that underneath all this I see that certain key individuals have met and will have taken a little further forward the collaborative and consensus based spirit that I perceive emerging from ME research in maybe the last two or three years. And they have not been locked out of the public relations process even if they are getting on with things without creating as much hot air as some others.

 

[jimells]

My best guess is the full draft is still being written. By releasing part of it the clock is ticking though. We will not have 30 days from the release of the full report, if indeed it is even released within 30 days.

No, this is all we are going to get. This report is a placebo. The idea that a real report could be written in a week, by a committee no less, is just silly.

I am impressed they managed to get the report on the internet before midnight Thursday. I recall all too well from my former life in the working world that it's impossible to get anything accomplished in December. Might just as well go on vacation until mid January...

 

[Jonathan Edwards]

@Jonathan Edwards Selecting these few statements above from your interesting response, I am reminded of what Dr. Nancy Klimas said in P2P about subgrouping as a means for advancing research. I wonder what the subgroups would be, of course, and wonder if they would be taken up and used by different researchers across the field? Dr. Klimas did not specify the kind of subgroups she has in mind during the P2P meeting but I believe she and other researchers in our field are starting to think this way.

In your view would it make sense to subgroup based on predominant, most difficult symptoms from the patient's perspective, or would it be a particular biological finding, such as a kind of immune overactivation, or immune underperformance, or degree of autonomic dysfunction, or brain scan finding, etc.? How do researchers select subgroups?

I think you subgroup according to whatever question you are studying. Sleep pattern disturbance might be a good subgrouping for studies looking at neural cycles in sleep. EBV serology might be good for immunotherapy studies. What you hope for is that certain biological subgroups will emerge that you can understand in terms of mechanism. So for inflammatory arthritis we subgrouped by 'seropositivity' or 'seronegativity' for rheumatoid factor. That was initially just because it seemed to link to severity. Then we realised that some of the seronegative patients had a completely different pathogenesis relating to the HLA-B27 gene. So now we have subgroups by known mechanisms. But before you get to that stage you are entitled to subgroup whatever way you think might test an idea. There is no need to agree on fixed subgroups - until you have a mechanistic reason to do that.

 

[jimells]

No. What I am saying is that even if we concede to them and assume that those studies are valid (and this is a debatable point as we all know) and even if we take the reviewers' inclusion/exclusion criteria at face value, when you look at their analysis it's not done correctly.

So what is the net effect of the mis-analysis on the evidence presented to the P2P panel? (I apologize if you already explained this.)

 

[Nielk]

Having read and thought I find it hard to formulate a response, but here goes. It seems that this was a committee that brought together some experts in ME research and some people with broader healthcare agendas, the latter presumably intended to provide balance and overview. In the event the output reflects the interests of the people involved - rather transparently.

The good news is that the experts include some people who are pushing for exactly the right things. The bad news is that the 'overviewers' seem to have muddied this with politically correct padding and off-target proposals of their own. Goodness knows what the political impact will be but my impression is that we should be pleased that a few very good minds got together to think about strategy and whatever they produced in terms of a report they probably benefited both themselves and the ME community by comparing ideas.

The people who have presented at the two day workshop (invited by the NIH) are not the ones who have creted/written this report. The panel of 5 who have produced this report are all from outside of the ME/CFS community. You can see their make up HERE. They are basing this report on the evidence review HERE and on the two day workshop HERE.

 

[Jonathan Edwards]

The people who have presented at the two day workshop (invited by the NIH) are not the ones who have creted/written this report. The panel of 5 who have produced this report are all from outside of the ME/CFS community. You can see their make up HERE. They are basing this report on the evidence review HERE and on the two day workshop HERE.

I realise that there are layers here but some of the stuff in the report is clearly a direct transcript of what some of the experts have said and I presume there was some dialogue. (at least at coffee time!)

 

[jimells]

So the most important question for me is what is the very best way forward for research

Dollars. That's all that's needed. Everything else is just re-arranging deck chairs on the Titanic. This illness is a solvable puzzle. We have people like Jonathan that know how to solve these puzzles, and would like to do so, but they have to eat, too. And buy stuff for their labs.

The report makes no mention of money or the role of NIH in withholding it. Without that the report is just a placebo, or kindling. Personally, I'll use it to light a fire in my wood furnace.

 

[Denise]

I realise that there are layers here but some of the stuff in the report is clearly a direct transcript of what some of the experts have said and I presume there was some dialogue. (at least at coffee time!)

FWIW - the panel members had minders who kept the audience and presenters at more than arm's length from the panel - even during breaks. (I attended the meeting and witnessed this. )

 

[Large Donner]

I realise how important it is for PWME to have their illness recognised

I am not sure you do when you put it like this.....

but producing some new criteria that are supposed somehow to be the best way to select cases of a hypothetical disease called ME, when it is likely that there are several of them, looks to me to be going in the wrong direction.

Hypothetical?

I am not at all suggesting using vague criteria for fatigue, except when it would be appropriate to do that.

Which is when exactly if you are not suggesting it at all?

I think criteria for any particular study should be much tighter then any set of criteria used for diagnosis - but tighter in a way that is relevant to that particular study.

I find this confusing can you elaborate about the, "but tighter in a way that is relevant to that particular study".

I think the P2P idea that variable criteria has wasted research is wrong.

Does £5 million on the PACE study justify this statement?

The waste comes from not thinking through the biological questions.

Yes but the whole point again is the assumption that most studies make any attempt to think through the biological questions and again the PACE study is a perfect example.

Do you think the the PACE study could have been spun the way it was if the patient selection was ICC ME and the cohort selection was independent of Peter White and co. For example if the selection of patients was made by people who wrote the expert letter to the NIH.

Its really simple, psychiatrists have hijacked this illness both in research areas and clinical practice by making no attempt to address the biological questions and its because of the multiple definitions they have been able to do this.

I think you need MEs to be tackled as the six or twelve overlapping diseases they are. That is what the key researchers are all agreeing on now I think.

Im not sure what you mean by this when you take into account the experts letter to the NIH. Who are the "key researchers", by name, you refer to above that are not on the experts letter?

If someone had persistent pain for which there was no adequate explanation in terms of damaged joints or whatever then for me that is what they had.

Yes but the thing is the whole point of a best criteria that can also develop to include the appropriate bio markers is not to end up at, "no explanation", and "damaged joints or whatever then for me that is what they had".

We simply dont want a diagnosis of "whatever".

hypothetical disease

Am I correct in saying that you are involved in the Rituximub IinME study. If that is the case do you know what criteria they are using? Secondly, what criteria would you like to be used for the study? Lastly although I understand that you may be using the term "hypothetical disease", in your own context could you clarify what exactly you mean by this.

 

[Sidereal]

So what is the net effect of the mis-analysis on the evidence presented to the P2P panel? (I apologize if you already explained this.)

Good question. Difficult to say without re-analysing the data which I am not currently in a position to do due to a crash.

 

[Nielk]

So when I treated the RA patients I was interested in the possibility that the inflamed swollen joints that they had, which were associated with a raised CRP and bone dissolution on X-ray was all due to antibodies forming complexes in the joints and might respond to blocking antibody production. They all had the problem I was theorising about. It did not matter whether anybody called it RA.

I think that the major difference here is that you were able to see visible damage in the patient as well as on testing. ME is basically an invisible disease and there are no accepted tests yet. How would you pick a problem to theorize about that effects ME patients? If you would pick for example sleeping problems and sleep study test results only, you will most probably see this same issues with patients suffering from all type of illnesses. The pathology though and cause of the sleep problems would vary, depending on what illness is manifested.

When you picked patients who had visible swelling of the joints, raised CRP and bone dissolution, chances are that the majority were suffering from RA. (no matter that you were not looking at it as RA)

I realise how important it is for PWME to have their illness recognised but producing some new criteria that are supposed somehow to be the best way to select cases of a hypothetical disease called ME, when it is likely that there are several of them, looks to me to be going in the wrong direction.

I am not sure why you would be calling it a "hypothetical disease called ME". We have the Canadian Consensus Criteria (CCC) which has been adopted by the majority of ME/CFS stakeholders, experts, doctors, researchers and advocates as the best criteria right now which describes the disease.

In addition, just because there might be subsets, does not mean that they are suffering from different diseases. With illnesses that affect multisystems, the illness will look different in many patients. With Lupus for example, the illness can involve different body systems and appear as if two patients are suffering from separate illnesses.

Doctors and researchers who have looked at this disease for decades, have decided that there are enough commonalities in patients to put together a set of criteria. What are you basing your comment on that there are likely several distinct diseases?

It might be that for your personal research purposes having a tight set of criteria is not too important but for us, the patients, it is vital.

Criteria are crucial in order to get a diagnosis from a doctor. It is crucial in order to get insurance coverage for care, testing and treatments. It is vital in order to be able to go on paid disability from work. To deny us this right is being neglectful of our needs.

 

[Nielk]

Several of the recommendations of this report mimic the ones from CFSAC. For example, the two recommendation of the June 2014 meeting of CFSAC are:

1. 1. CFSAC recommends that the NIH adapt the architecture of the National Autism Research Database (NDAR) to setup and
      provide ongoing support for a data and bio-bank sharing platform for ME/CFS research. This platform should allow for both phenotype and biologic data.
   2. CFSAC recommends that the NIH issue a Request for Applications (RFA) for ME/CFS by November 1st, 2014, or as soon as feasible, to address the gaps in ME/CFS knowledge and research. The RFA should consider current known gaps in knowledge for the following areas:
   • Provocation designs where symptoms are triggered through standardized challenges involving exercise, cognitive tasks, and mental stressors. These designs appear to be more likely to identify symptom to biology relationships in comparison to assessments done in resting states.
   • Ambulatory monitoring of symptoms, activities, behaviors, and physiological states that identify associations between biological and behavioral measures, e.g., daily fatigue ratings and cytokine fluctuations.
   • Network analysis of dysregulation of multiple bodily systems, such as the neuroendocrine system, the central nervous system, the autonomic nervous system and the immune system.
   • Natural history studies aimed at identifying the genetic triggers and causal factors of ME/CFS.
   • Treatment trials that address both clinical and biologic outcomes.

1. Here is the October 2014, reply from Sylvia Burwell - http://www.hhs.gov/advcomcfs/recomm...e-from-sburwell-june-2014-recommendations.pdf

Where she basically explains why both recommendation will not be complied with due to lack of funds.

The recommendations listed in this draft agenda are not new. The ME/CFS stakeholder's community including the federal CFSAC has asked for these repeatedly. We have been either ignored or denied. Do you really think that now, that 5 people outside of the community who have been selected by the NIH to compose this report, all of a sudden the NIH will say YES, YES, YES.

Sylvia Burwell will say, now that we have this highly sophisticated, scientifically based and sound 19 page typed report by 5 outsiders, I will magically pull out 100 million dollars out of my hat in order to fulfill these recommendations and to advance the science for ME/CFS. (???)

 

[Nielk]

CFSAC recommendations March 2014. http://www.hhs.gov/advcomcfs/recommendations/03112014.html

The Chronic Fatigue Syndrome Advisory Committee (CFSAC) unanimously stipulated that all references to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in these recommendations are defined by the 2003 Canadian Consensus Criteria (CCC)1.

1. CFSAC recommends that the Secretary fund ME/CFS commensurate with the epidemiologic prevalence and economic burden that this disease imposes on American society. 2,3

2. CFSAC recommends that HHS provide opportunities for dissemination of information through the development of a curriculum at all U.S.-based medical schools providing the tools needed for physicians and other medical professionals to recognize ME/CFS as defined solely by the 2003 CCC and to make appropriate referrals.

3. CFSAC recommends that funding be allotted to the appropriate agencies that can best develop teaching modules featuring ME/CFS patients with complex presentations as defined by the 2003 CCC.

4. CFSAC recommends that HHS provide funding through Health Resources and Services Administration (HRSA) and other agencies to support integrative medicine programs featuring learning about ME/CFS patients as defined by the 2003 CCC.

5. CFSAC recommends that HHS fund through appropriate agencies novel programs such as “Project Echo”4comprised of experts and/or multidisciplinary teams with expertise in ME/CFS that reach areas where patients do not have access to adequate clinical care for ME/CFS as defined by the 2003 CCC.

6. CFSAC recommends that HHS provide funding to gather requisite data (prevalence rate/provider attitudes and knowledge, etc.) regarding ME/CFS patients as defined by the 2003 CCC through established primary care associations such as the American Academy of Pediatrics; the American Academy of Family Practice; the American College of Physicians; the American Board of Family Practice; and the American College of Obstetrics and Gynecology.

7. CFSAC recommends that HHS support CFSAC’s efforts to continue to amend CDC website information as has been discussed previously5.

How many of these have been implemented?

 

[Jonathan Edwards]

FWIW - the panel members had minders who kept the audience and presenters at more than arm's length from the panel - even during breaks. (I attended the meeting and witnessed this. )

How bizarre. The main reason for a committee to have contact with presenters would be, to my mind, to be able to work out if they were talking through their hats (to be polite). Why have minders? Maybe things work differently across the Atlantic.

The report seems to be an account of the interests of about 6-8 people. The code words are easy enough to read. It is intriguing how this came about. Maybe what matters is not the committee that wrote the report so much as the committee that appointed the committee that wrote the report or even the committee that appointed the committee that appointed the committee that wrote the report - except that that is probably the same people who wrote the report in some cases. Not to mention the committee that invited the experts...

Interesting anyway.

 

[Sing]

Government officials are governed by politics. The art of political leadership, I have heard, is to see where the crowd is going and to jump out in front of it. The crowd in our field has in recent years been getting its act together with more and better research, at the scientific end, and a lot more cohesion and focus from the patient end, thanks to forums like this one. The government folks have noted that the tide has turned and now it looks to be politically safe and appropriate for them to start to play the role they should have been all along--furthering scientific research. The $1 million dollar pricetag for P2P might be viewed not only as a huge waste of money, but as a political indicator of a willingness to change direction, to go where the crowd is now going, to give the appearance that they are functioning as leaders. Let's help them know exactly which way THIS crowd is going by responding to the draft report.