Dr Ron Davis on why his NIH proposal was rejected

[snowathlete]

Dr. Hanna noted that the NIH review process requires a testable hypothesis and researchers must explain how they will accomplish the study. Research proposals must rank in a respectable percentile to be funded. CFS research at NIH will only grow if more grant applications are submitted, accepted, and funded.

(1st CFSAC meeting minutes, Sept 2003)

If this info is still applicable in 2015 then I think this shows a big part of the problem; what Dr Davis is proposing, as I understand it, is a new aproach to disease research: test absolutely everything that technology allows. Normally you have a hypotehsis and your aproach is quite narrow as a result, and that aproach may have made sense in the past, but we've reached a point where you can take a sample and find out everything there is to know about it and it is affordable to do that. It suggest that the NIH is behind the times in this regard, because such an approach doesn't require a theory about what's wrong. You simple look at the results and see what is wrong. That might tell you directly what is wrong, or it may only tell you where to look. It also potentially gives you a useable biomarker you can use for diagnosis. It's hard to see how such outcomes wouldn't be a leap forward.

 

[Hutan]

You could look at the study in another way that does result in a testable hypothesis:

"ME is a biological disease and so people with ME will be biologically different from healthy people. The sickest people with ME will show the biggest differences. And if we look at a very broad range of possible biological tests in these sickest people, we will find these differences.

 

[Hutan]

What I mean is, if the NIH wanted to fund research to find the cause of ME, it wouldn't take much thinking to fit Dr Davis' proposal to the NIH requirements. If there wasn't enough detail because this was a preliminary proposal, then the NIH could ask for more detail.

If the NIH wants to proactively fund research to find the cause of ME, neither of the two reasons given would be a problem. It's hard to believe that the NIH has a problem specifically with the competence of Dr Davis and his team. So, I think the NIH needs to be pressed further to explain what the problem really is.

I hope the new guy who has the job of pushing for ME research, the one who thought the $5 million funding was a typo, will find out for us. (and make the problem go away)

 

[Sasha]

I hope the new guy who has the job of pushing for ME research, the one who thought the $5 million funding was a typo, will find out for us. (and make the problem go away)

Do you mean Zaher Nahle? I thought his job was researching, rather than pushing for research (though he seems to be doing a great job on advocating for more money as a sideline!).

He's on the forum but I can't remember his username to tag him.

 

[Hutan]

Do you mean Zaher Nahle?

Oh yes, I did think it was Zaher Nahle. I thought from his job title and his comments that he was a research facilitator but I probably have that completely wrong. I haven't got my head around the US ME organisations at all.

I do hope there is someone on our side masterminding a strategy to get the $5 million to grow and allocated wisely. (ie liaising with the NIH and potential researchers to make things happen).

 

[RustyJ]

In the recent Rituximab open label study, they added about 10 Fukuda CFS patients to the 20 patients from the previous study. The response rate in both studies was the same.

And the idea that CBT and GET are the right thing for some patients is laughable. In the PACE trial nobody recovered as shown by absence of improvement in outcomes such as fitness, walking test, employment, etc.

I think reality is more nuanced than the "ME = real illness, Fukuda CFS = garbage bin diagnosis with many neurotic cases" viewpoint.

I'm also surprised that a patient so readily dismisses another patient group as not having a real illness. You should know better than this.

I don't disagree with the principle of what is said here, but from memory, severe ME/CFS has high non-response rate with Rituximab. From what I read, it was not looking too good for severe cases as a treatment.

 

[Scarecrow]

He's on the forum but I can't remember his username to tag him.

It's znahle.

 

[medfeb]

What I mean is, if the NIH wanted to fund research to find the cause of ME, it wouldn't take much thinking to fit Dr Davis' proposal to the NIH requirements. If there wasn't enough detail because this was a preliminary proposal, then the NIH could ask for more detail.

If the NIH wants to proactively fund research to find the cause of ME, neither of the two reasons given would be a problem. It's hard to believe that the NIH has a problem specifically with the competence of Dr Davis and his team. So, I think the NIH needs to be pressed further to explain what the problem really is.

I'd agree.

In NIH's current program announcement, found here, NINDS states its interest in research as follows:

"NINDS is particularly interested in encouraging multi-PI interdisciplinary research directed at the pathogenesis of ME/CFS affecting the brain, autonomic, and the peripheral nervous system.
Examples of topics for which there are gaps in knowledge and research opportunities are:
1. Differences in CNS-related biomarkers between new onset and established ME/CFS patients and appropriate comparison groups.
2. Identification of biomarkers in cerebrospinal fluid, blood, urine, etc. that can identify physiologically relevant subgroups of ME/CFS.
3. Studies elucidating the characteristic autonomic abnormalities seen in the central or peripheral nervous system of patients with ME/CFS."​

While I have no idea what grant mechanism Davis applied to, I'd think his work appears to satisfy NINDS's interest in this disease as expressed here.

 

[jimells]

Maybe I'm misunderstanding this, but the Program Announcement has already expired. I vaguely recall Jennie Spotila writing about this some time ago.

Expiration Date
New Date February 25, 2015 per NOT-OD-15-006 (Previously: October 25, 2014)

 

[jimells]

Maybe one reason that applications can't get through the review process is buried in the PA:

ME/CFS is one of many co-morbid chronic pain conditions, including temporomandibular joint disease, vulvodynia, endometriosis, fibromyalgia, interstitial cystitis/painful bladder syndrome, chronic prostatitis/chronic pelvic pain syndrome, and irritable bowel disease. The relationship to these other diseases remains to be further elucidated through epidemiological and basic-science research.

This doesn't sound much like the illness I have, which is clearly neurological and not a "co-morbid chronic pain condition", whateverthehell that means.

What do poorly-informed reviewers conclude when they compare this description to grant applications looking for immune dysfunction, etc?

 

[Hutan]

Cort has provided a useful summary of ME/CFS projects funded by NIH.

http://www.cortjohnson.org/blog/2015/08/23/lipkin-nih-grants-chronic-fatigue-syndrome-2015

It is a much longer list than I had realised. It would be really interesting to see what funds are committed for each project, for this year and the years going forward.

Could it be that, with the limited budget for ME, Dr Davis' project was seen as just too large a commitment of funds to go to one research team?

In any case, the NIH statements about there being a lack of good projects being put forward seems very odd.

 

[jimells]

Could it be that, with the limited budget for ME, Dr Davis' project was seen as just too large a commitment of funds to go to one research team?

Just like when you ask the boss for a raise, all of a sudden the agency is broke and bleeding money. You are not supposed to notice that the boss' wife just bought a new Cadillac or that Congress just added Two Thousand Million dollars to the NIH budget, which is now about $32 Billion.

Yes it is too large a commitment of funds if the goal is to not increase the research budget. Official NIH responses to the CFSAC recommendations clearly state over and over that "there's no money for X". They have also clearly stated there will be no increase in the budget when they flat out rejected CFSAC calls for an RFA, which is supposed to include a dedicated pool of money.

I can't imagine how they could more clearly announce that they hate us and they are not going to help.

 

[Gingergrrl]

Could it be that, with the limited budget for ME, Dr Davis' project was seen as just too large a commitment of funds to go to one research team?

Then why couldn't they have partially funded the project instead of flat out rejecting it? I don't know the answer myself but it seems like the reasons they gave him were nonsense and they just had no intention of ever funding this project yet random unknown projects got funded (I don't mean Lipkin of course!) but some of the others.

It seems like they funded a lot of exercise studies with mild patients yet rejected the one study to look at severe patients who are bed bound and cannot eat or breathe or walk. Why is this? (Am not directing this at Hutan, just venting.)

 

[Seven7]

Did you see the list where they approved another exercise program (for the NOVA center)?? But I dont remember if that one was for the severe ones.

 

[Gingergrrl]

Did you see the list where they approved another exercise program (for the NOVA center)?? But I dont remember if that one was for the severe ones.

I don't think those with severe ME can participate in an exercise study and AFAIK only Ron Davis' study which got denied was going to study this population by coming to their homes to do testing.

 

[panckage]

You could look at the study in another way that does result in a testable hypothesis:

"ME is a biological disease and so people with ME will be biologically different from healthy people. The sickest people with ME will show the biggest differences. And if we look at a very broad range of possible biological tests in these sickest people, we will find these differences.

I don't believe that's what they implied. A study like that is referred to as posteriori study. Posteriori studies have low statistical power and have a high chance of spurious correlations. Seeing as the the trial will have only n=40 (is that correct?), from a statistical standpoint it is pretty much dead in the water.

That being said the study is not a bad idea as a starting point, but with a cost of $25,000 per n I think a study like this would need special permission to get funded

 

[Hutan]

Yes, of course it is likely that some spurious correlations would be found. Yes, this type of experiment generates hypotheses for future testing rather than delivering a tested treatment.

But a comprehensive analysis of 40 severely affected people with a very homogeneous illness is likely to tell us much. A homogenous sample population and a large effect size can overcome a small sample size.

Would you dismiss a finding that 39 of the 40 people had a result for a parameter greater than 2 standard deviations from the mean for healthy people as not worth thinking about? If that variation in the parameter could not be explained away as being a result of being bedridden for years, wouldn't that be a finding to help guide future research?

Even negative results such as the absence of certain pathogens could potentially save many millions of dollars spent on research on things that aren't relevant.

Set the cost of this research against the annual economic losses resulting from the illness in the US, not to mention the enormous suffering throughout the world. Few investigations of severe ME patients have been done to date. The team that would be doing the work is high quality and highly motivated to find real results. Seems like a good investment of government funds to me.

@panckage, what special permission for funding are you talking about?

 

[jimells]

That being said the study is not a bad idea as a starting point, but with a cost of $25,000 per n I think a study like this would need special permission to get funded

Fortunately the study is now largely funded in spite of NIH intransigence. An anonymous donor just wrote a check for $500,000 in addition to other privately raised money. I doubt our anonymous benefactor has $32,000,000,000 per year to play with, like the good Dr Collins, so they must really believe in the usefulness of the study.

 

[Bob]

Fortunately the study is now largely funded in spite of NIH intransigence. An anonymous donor just wrote a check for $500,000 in addition to other privately raised money.

At $25,000 per participant, i think the $500,000 donation pays to investigate 20 patients. They are seeking an initial $1m for the first stage of the study, so I'm not sure if the first stage is largely funded? (I'm not sure how much they've raised in total?)

Also, the End ME/CFS Project is seeking $5m a year for 5 years. So the End ME/CFS project is nowhere near fully funded.

 

[Scarecrow]

Also, the End ME/CFS Project is seeking $5m a year for 5 years. So the End ME/CFS project is nowhere near fully funded.

I hadn't realised it was $5M per year, I thought it was $5M over 5 years. Long, long way to go!