David Tuller: Trial By Error: “Talk is Cheap,” Patients Tell NIH

What I was wondering @Jonathan Edwards, is what you mean by "objective clinical documentation of the illness in day to day circumstances". I have my picture of it: document signs, symptoms, testing, on a daily/as lived basis - what happens to pwME in their real world, and wrap this up in published studies. If daily activity patterns encompass this, then I understand what you mean.

My understanding of your point about "research groups are starting at the wrong end" is that they need to do basics first: objective clinical documentation of the day to day circumstances.


You are probably aware the CCC, page 18 and 19 includes Neurally mediated hypotension (NMH), Postural orthostatic tachycardia syndrome (POTS), and Delayed postural hypotension under the OI heading, as "commonly seen in ME/CFS patients":

http://www.mefmaction.com/images/stories/Medical/ME-CFS-Consensus-Document.pdf

I don't have any explanation for these various shades of OI in our population. I have had a couple tests, one in a preliminary study, and one with a specialist that documented an abnormally high HR increase with standing (POTS). Early on I had a doctor's office test that documented NMH.


I get the impression your view is that researchers are rushing ahead, but do not have adequate documentation of physiological problems. This is concerning and confusing, as many of us turn to the CCC, and other case definitions for an overall review of research information about physiological abnormalities.

I thought the basics were already done.

 

Not sure if this is useful but in case - have you seen David Systrom's interview by Llewellyn King? Systrom discusses the findings of invasive CPET testing that he states indicate pre-load failure on exercise testing. He also notes small fiber neuropathy in half and also a failure of oxygen extraction.

https://www.youtube.com/watch?v=FMaKfv8peww

(Minute about 18-21)

 

Fixed that for you...

 

I agree, @rvallee about internal opposition. We have been told it was very difficult to collect enough money to fund the new research centres.

And, researchers have been told they will blow their whole career if they work on ME. I think it is the unique individual who is curious enough, and brave enough to forge ahead in untested waters. Many take the safe route, and who can blame them really - it's a big investment.

Immunologist, James Allison is one such brave individual, who went against traditional wisdom in his field, and eventually won a Nobel prize; now others in his field a flocking to this way of thinking: https://www.nature.com/articles/d41586-018-06751-0

Other than more scientific results paid for outside the NIH system, perhaps what is needed to change the minds of those who still say ME is fake, is for change in other areas regarding this disease. For example, a retraction of the PACE trial. Or other governments to make positive moves - biomedical funding, medical education, public awareness.

The NIH is the largest medical research granting agency in the world, but I think we need to pay attention to other countries as well. And, somehow, step up our own funding.

 

In regard to the NIH in-house study, the stated recruitment requirements are "Those with ME/CFS that started after an episode of infection who have severe symptoms based lasting between 6 months to 5 years" - source, https://mecfs.ctss.nih.gov/.

I'm not surprised they are struggling to recruit, 1, in my opinion chances are that a good portion of those are diagnosed within a 5 year time frame will probably have something other than ME, 2, as said previously elsewhere on this forum, new patients are unlikely to be aware of research participation opportunities like this, and 3, they are limiting themselves to those with severe symptoms when severe, to most patients, means that they struggle to leave the house, let alone travel and stay somewhere for effectively two weeks.

They should be applying some self-awareness and asking themselves why exactly they are finding it so hard to find patients to take part, they will then identify issues that patients face and, if nothing else, this then could become part of the results of their study.

 

The Johns Hopkins patient handout on Orthostatic Intolerance (see http://www.dysautonomiainternational.org/pdf/RoweOIsummary.pdf from the Dysautonomia International website) says that a patient can be diagnosed with either NMH (Neurally mediated hypotension), or POTS (Postural tachycardia syndrome), or with both.

I have no idea whether this is correct. And I have too much brain fog to debate medical issues so I can't join in discussion.

I'm just posting this reference in hopes that it might be helpful to someone out there. I know that the whole area of autonomic issues can be very confusing. For a while there were some doctors who were using the diagnostic label COI - Chronic Orthostatic Intolerance.

 

This argument makes no sense to me from an ethical standpoint.

Its incumbent on someone to fund research in this Illness. Since it is not profitable for thr commercial sector , since we don't even have a clear idea of etiology and hence are very far away from drug trials, it makes sense for the government to lead , and throw money at exploratory research that is going to lead to a clear understanding of the disease.

I mean --who else is going to do it?

The ME research field has suffered from a scarcity mindset imo. Every researcher in their own silo with their own pet theory that they think prevents them from looking broader because they only have so much funding to spread around.

ME is a disease with lower quality of life than most diseases. If one only considers mortality rate, I guess it would be hard to see ME as a genuine public emergency like the AIDS crisis. Although patients do die from suicide (which may be taken as evidence that it deserves the "psych " label although suicide when faced with an incurable disease like this is clearly rational) at a higher rate than the general population , they dont tend to die directly of this illness. But if you go by quality of life and also amount of people affected , this illness would be seen as a public health emergency. I'm aware of NIHs rules for funding and that they generally don't make allocations for specific disease but I'm sure that agencies like NIH can make exceptions in the case of a public health crisis. Or at least appeal to congress for more help. So my question to you is--do you consider this an emergency/crisis or not? If it's not a crisis, i guess the "wait and see" approach is morally justifiable.

Sure, there are many low quality studies. And some of that may not be due to scarcity of funding but much of it may be. I mean, I'm not sure that science is exempt from laws of political economy.

And yes, we don't want to waste money by throwing infinite amounts of it blindly at a disease. But I'm not convinced by any ethical argument that ME funding could be a significant waste of taxpayer dollars or something. The US military and intelligence agencies have incredibly huge budgets and are largely unaccountable financially. I bring this up to make two points. A) so much more could be spent on any given disease without coming close to the waste in other sectors by government and B) While there is a grotesque amount of waste there and it goes largely toward furthering evil , in my opinion, the US military gets results. One can say there's waste, and it's basically unarguable. But I can't imagine the US being a world bully or cop or superpower while spending what they spend on ME on any of their projects. So maybe if we don't have scarcity in the field and just spend a lot, we can attract good scientists to it. As it is, the uncertainty re: the etiology is only one of the reasons the field is unattractive to scientists, I'm sure the funding has a lot to do with it.

 

People who actually want to get an answer, rather than just have a job in a lab or be famous.
That has been the reality of science for centuries and nothing much has changed. From 1960 to 2000 there was a huge technological explosion that justified hundreds of thousands of scientists who did nothing much more than read out the next protein or gene sequence. That is now over. What are needed are ideas that work and they cannot be bought.

It may sound strange but I was brought up in science and spent my life in science. I have in my study the cabinet used by the scientist who set up the UK Medical Research Council, with drawers for pipettes and chemical reagents. My own work has had a spin off running in to tens of billions of dollars but the money I had in specific grants for that was about $20,000 over 20 years - enough to get lunch at work.

If the NIH spends 500 million on ME research and nothing comes of it then we can guarantee that they will say what the MRC said in 2002 - we have poured money into biomedical research and got nothing out so let's forget it.

My impression is that the big government bodies are currently being quite intelligent. They are asking around for everyone's views on what might take us forward, and they are listening. Ideas are being taken up. The real limiting factor I see at present is the shortage of clinicians with experience of ME who have a good enough understanding of how to gather reliable evidence. The pure scientists are ready to get started but the clinical link up is weak. The solution to that is to fund a decent clinical service - and that I feel very strongly is needed.

 

Could you expand on that please. Why do you need clinicians and clinical backup in order to undertake medical research. Surely the clinical side of things is dependent upon there having been adequate research on which to base the clinical side of things. I know I'm must be missing something, because I'm fully aware you know what you are talking about .

 

It is mostly about recruitment of a consistent cohort of people to study. In the UK the ME Biobank team have seen years developing a consistent approach, the lynchpin of which is Caroline Kingdon, who sees all the subjects on a regular basis and has the advantage of not having any particular theoretical axe to grind. But when you leap to a 20,000 GWAS there is no reliable network of the same sort.

In the US I get the impression that there are islands of clinical expertise but studies are often done recruiting through the net, which is far from ideal. I don't think private practice blends that well with the sort of basic studies that need doing. Private physicians have to see something and that is likely to flavour both recruitment and analysis of data.

 

Clinicians and researchers tend to share the human trait of not seeing what they don't want to see. The NIH seems to enjoy an inexhaustible supply of this trait.

 

Indeed, which is why I am sceptical that the solution is to ladle more money through the NIH into projects just for the sake of it.

 

I don’t believe in just shoveling money into a disease either, @Jonathan Edwards . You just end up with poor science. But I do believe that NIH can do a number of things to stimulate the field. These actions are a part of NIH’s current methods and can easily be utilized for our disease.

I have never been one to call for hundreds of millions of dollars right away, for the exact reasons that you have mentioned. But NIH can stimulate the field so that there is annual growth in high quality research. I do believe that they have that responsibility.

These are the 5 actions called for in the petition:

1. Provide set-aside funding for ME to accelerate research
   
   
2. Organize meeting of ME experts to reach consensus on patient selection methods and criteria
   
   
3. Fund the identification and validation of biomarkers
   
   
4. Fund a clinical trials network and treatment trials
   
   
5. Address disease stigma and lack of clinicians impeding research
   

I think that every one of those is a valid goal. NIH could do each of them very easily. I think that they should.

 

My main hope about that project is that if some clinician scientists immerse themselves in the detail of measurement they may get a better grasp of what to focus on. They may chance upon some correlation that everyone has missed. I thin there is a place for that sort of intensive investigation of lots of things.

 

Regarding point 1, I understand that it is the US congress that has to ask NIH to set aside funding. Lipkin told us to lobby congress years ago already. He said that is how other patient groups achieved set aside funding.

 

I think these are not unreasonable but I would suggest some variations:

1. Setting aside funding does not in itself get things moving, other than attract scavengers. What I think NIH should do, and MRC is now doing, is to set up a working group of people not directly involved in ME research but with the job of actively looking out for and setting up dialogue about potential projects on the understanding that if projects materialise they will be guided through the system without the dog eat dog competition otherwise operating. Money is there in the pot. Rather than saying ring fence X million of those dollars I would suggest any amount is on the table for facilitated access.

2. Consensus amongst clinicians is never a very good idea. Clinicians are muddle headed about criteria and patient selection and consensus always ends up as a compromise at the lowest common level. Selection criteria should be different for every study. I would forget this one. What we want are researchers who know why they are choosing certain criteria, not ones who follow like sheep.

3. Finding biomarkers is the key. But I biomarker to be any use is something that points to a mechanism. So far we done't have any and nobody knows where one is going to be found. So this is a great idea in principle but it does not guide us where to go. You cannot say you will go out and discover that anti-proteinase 3 antibodies are a marker for Wegener's granulomatosis - someone has to happen upon the finding.

4. Clinical trials are important but what do we try? I am not convinced I know of anything worth trying in a major trial at present. Some money could be spent checking the loose ends on IVIg, ampligen or anti-virals but I doubt it will get us very far. What I think would be good would be to set up a trial system involving professionals with no personal interest in any theory behind what is being tried. So on balance I tend to go with this one and say a unit should be set up that could get going tying uo some loose ends initially and keep an eye out for new projects coming in.

5. I don't know how you address stigma. It is a bit like persuading people to vote democrat. People don't necessarily play ball. But I am very much in favour of recruiting more clinicians. In private medicine I am not sure how that would work since there is no treatment to offer. In a single payer system like ours it ought to work but even here we have the problem of how we justify paying for a service with no treatments. This absolutely needs addressing, just for care, but also to provide a pool of clinicians capable of doing research.

 

I’m glad that you mentioned that, @strategist , because there are two types of set side funding. Within NIH, there are programs like the RFAs that resulted in the Cooperative Research Centers. NIH can internally set aside funds to fill particular research needs. The proposals are still peer reviewed, but are only compared with other proposals within the same area of study. They do this all the time and that’s what ME Action is asking for. Set aside funding is meant to boost research by attracting good researchers.

Congressional funding is much harder to obtain and is usually for much larger amounts. That would take much more time to achieve, but advocates are working in Congress in hope of obtaining it.

 

I think LDN would be more important as there hasn't been any clinical trials on it yet. Some people say it's a helpful treatment.

Re. consensus about illness definition, I would say we need the opposite, a unity movement within the patient community so that we can focus on goals that really matter.