NIH ME/CFS Advocacy Call - July 2017

Transcript

NWX-NINDS

Moderator: Marian Emr
07-10-17/11:00 am CT

Coordinator: Welcome and thank you for standing by. At this time all participants are in listen-only mode until the question and answer session of today’s conference. At that time you may press Star 1 on your phone to ask a question. I would like to inform all parties that today’s conference is being recorded. If you have any objections you may disconnect at this time. I would now like to turn the conference over to Ms. Marian Emr. Thank you, you may begin.

Marian Emr: Thank you and good afternoon. My name is Marian Emr and I’m the Director of Communications and Public Liaison at the National Institute of Neurological Disorders and Stroke here at NIH. On behalf of the NIH, I’d like to welcome you to this afternoon’s teleconference and to thank you for your interest in participating in this discussion with us today.

Here at the table this afternoon we have Dr. Walter Koroshetz, Dr. Avindra Nath, and Dr. Joseph Breen. Dr. Vicky Whittemore is joining us by phone. Dr. Koroshetz will introduce the speakers, each of whom will make some brief remarks, after which we’ll open the phone for your questions. We’ll try to keep our remarks short so that we can answer as many of your questions as possible in the time we have available to us this afternoon. Now, Dr. Koroshetz.

Dr. Walter Koroshetz:   Good afternoon everyone. Thanks for getting on the line and we wanted to brief you regularly about the developments here at NIH related to ME/CFS research. And we’re always excited to do that and answer questions as best we can. This afternoon we’re lucky to have Dr. Avi Nath here with us in the room today and he’ll provide some updates on the NIH intramural study.

As people know we’re very excited about the RFA that’s out. The idea is to seed ME/CFS research in a coordinated way across the country by setting up a consortium of investigators, which will be coordinated out of a clinical coordinating center. Data will go into a data coordinating center and the groups will work together on projects as well as use their special expertise to discover the things which we think will be important to understand ME/CFS and get to its treatment.

So it will be a combination of research done at the institutions and also in a coordinated fashion and also a coordinated project. So we’re really excited about this. The grants are in and soon to be reviewed. We’ve gotten also interest from and are discussing, early stage discussions, with international funding agencies that may be interested in joining as well as some of the other agencies in the U.S. So we’re hoping this is the beginning of something that will really transform our research in ME/CFS and have to underline that this is just the beginning. This is seed coordination, to hopefully seed research throughout the U.S. on ME/CFS. Since our last briefing Dr. Collins and I worked together on a blog for his Director’s Blog about ME/CFS entitled, Moving Toward Answers in ME/CFS. And it goes over a lot of things that we’re doing at NIH that we’ll be talking about today.

And I also wanted to mention something that’s a little bit of a sensitive issue but an important issue for brain research and ME/CFS. As everyone on the phone knows it’s really quite a mystery as to what’s going on in the central nervous system in ME/CFS and we can only get answers to many questions if there is brain tissue available for researchers to actually examine the tissue and try to see evidence of either immune activation, or cell death, or changes in connections that are related to the disease.

And so I wanted to mention that we have a NeuroBioBank that NIH has been funding for a number of years now. And we are interested in trying to work with folks on the outside to help us get tissue on ME/CFS into the NeuroBioBank. We’re very happy to have the help of the Brain Donor Project. Tish Hevel who has also been working to try and get a greater acknowledgment around the country of the importance of brain tissue for neuroscience research. And in her blog on March 2 she actually singled out this need for ME/CFS tissue to move forward as well.

So I just wanted to let folks know about that. The NeuroBioBank blog is now current. If you just go to NINDS and look for the Director’s Message, you’ll see “The NIH NeuroBioBank: Addressing the Urgent Need for Brain Donation”. And that’s about many different diseases, not just ME/CFS, but multiple other neurologic and psychiatric diseases as well.

So those are the main things I wanted to get out as we start. And we’re always eager to hear from folks and so we’ll keep our remarks very brief before opening the phone lines for questions. And with that I’d like to turn the line over to Dr. Nath to give an update on the Intramural ME/CFS protocol. Avi?

Dr. Avindra Nath: Yes, thank you Dr. Koroshetz. So as Dr. Koroshetz mentioned I oversee the Intramural Program for ME/CFS. And I’m happy to state that it’s gone on remarkably well, much better than I had actually anticipated. We’ve had over ten patients come through, controls and patients with ME/CFS, and everything has gone very, very smoothly.

We have put them through a very extensive workup schedule. Each one of them has been here for over a week. But that’s just the screening part of the protocol and now based on that data that we’ve collected on them, we’re now bringing in patients for a complete workup. And so the first of those patients will come on July 26. So we’re looking forward to that.

Dr. Walter Koroshetz:   Okay. Well thank you, Avi. And now I would get an update from Vicky Whittemore about the RFA so far.

Dr. Vicky Whittemore: Yes, good morning everyone and I welcome you to the call as well. Just to give you an update on the timeline for the RFAs, they will be meeting and reviewers have been invited and the study section will be meeting at the end of July to do the review. And then the Working Group will come together in August to look at the reviews and determine the funding plan and the recommendations for funding then will be taken to the appropriate NIH Institute Council meetings in September, with the hope that we can then get the Notice of Awards out by the end of September, which is the end of our fiscal year.

And so then our goal would be to have a meeting of the investigators and the groups involved in the funded applications, including those people funded for the Data Management Coordinating Center, in the fall to really launch the project and get things moving in the right direction right from the get-go.

So just a couple of other updates that I can provide for you. So as many of you also know we’ve been working in partnership with the CDC and our contractor AMMES to develop the Common Data Elements for ME/CFS. And these working groups, there are now several subgroups that have been working for several months now to review various aspects of ME/CFS and to put forward recommendations for instruments to be utilized.

And if those instruments are used to measure something like postural orthostatic hypertension or various other aspects of ME/CFS, then the data would be collected in a standardized way. And the goal being that studies, results across studies can be compared directly if people are using a common language or a common way to report their data. So that project is coming along very well.

And our timeline for that project is that we will be finalizing as the working groups the recommended common data elements this fall and then providing those to the public for public input prior to finalizing the initial draft. And I say finalizing the initial draft meaning that this will be a living document and living project that will be modified and changed over time as we learn more about ME/CFS.

And then the last thing I’ll comment on is that I and Andrew Breeden, my colleague at NINDS, had the opportunity to go to the Invest in ME Conference in England, in London, in the end of May early June, which was an international research conference on ME that was very, it was fantastic. And I think that some of the science that was presented there is just really promising in terms of really beginning to understand the underlying mechanisms that can then cause the symptoms of ME/CFS.

And it was very interesting because many of the investigators are coming at this, at the issue of ME/CFS from very different directions, which I think is going to all come together to show us that it is heterogeneous disease with potentially many different mechanisms that all lead to very similar symptoms that we’ve been calling ME/CFS but likely have different underlying causes.

And I was asked and volunteered when we were on the most recent CFSAC call about these various subtypes that are emerging from the research. And we’ll be providing my colleagues on the working group and I will work together to provide an update and to discuss that in a little more depth at the next CFSAC meeting in December.

And the last thing I would mention, as Walter mentioned, we’ve been having some discussions with some of our international partners. And while I was in the U.K. I had the opportunity to meet with a representative from the Medical Research Council in the U.K. as well as a representative from the National Institute of Health Research, which is more of a translational branch of their research funding agency to discuss potential ways that we could collaborate and work together to really further research on ME/CFS.

So I think it’s really very exciting that there’s increased awareness, increased discussion and increased collaboration across countries to really move and as Walter said transform research on this disease. So I’ll stop there and hand it back to Walter.

Dr. Walter Koroshetz:   Great. And next I wondered if Dr. Breen could tell us a little bit about the interest that he has seen at the Clinical Immunology Society meeting and the SLEEP meeting?

Dr. Joseph Breen: Yes, that would be great. Thank you very much. I’d like to tell you a little bit about two recent scientific meetings that Vicky and I attended. The first of which was in early June. We attended a SLEEP meeting in Boston. And specifically we were asked, Vicky and I were asked, to speak at a session that was called Sleep Cytokines and Fatigue.

And the session was really designed around immunology and fatigue and how they relate to sleep. And I think that there was an overlap with chronic fatigue that’s not 100 percent but I think there were some clues that can be gained by looking at fatigue research, which is why they really invited both Vicky and I to participate. And there’s a lot of preliminary and unpublished data that’s presented in these type of meetings, but the upshot I think was that there is work, for example in the development of a mouse model for fatigue and also some really interesting work using a roundworm to look at cytokine-induced fatigue that may help us understand mechanisms which are common with chronic fatigue.

So there was some very interesting basic science as well as clinical science that was more specifically talking about chronic fatigue. But we ran the gamut of very basic mechanistic approaches that were discussed as well as more clinical. So I think again that to revisit the theme that Vicky mentioned, you know, this is a complex problem, probably has more than one etiology. And so looking at this from different approaches and another field, frankly, like the people who looked at fatigue and sleep and bringing in things that are more commonly studied with chronic fatigue, like inflammation, I think will be an advantage.

The second was just about a week later in Chicago. There was a session that Vicky and I organized at the Foundation for Clinical Immunology Society meeting. And this is really a very clinical meeting where the intention was to discuss the state of the science in terms of immunology and basic immunology as well as clinical immunology in the front of a very clinical audience to try and draw in some connections and develop new collaborations that would be helpful in the area.

The session was kicked off by Beth Unger from the CDC with talking about her program and chronic fatigue overall. And then we heard some of the work that’s supported by Mark Davis at Stanford. And Mark has really pioneered the way to go from how the immune system senses either an external or internal antigen and then actually how that response is generated.

And it’s very groundbreaking work in that he can go from not knowing what the body is responding to, to actually doing detective work and tracking back to find where the original response was. For example, in a large cohort of chronic fatigue patients he has now found a number of new antigens that correlate with disease. And he hasn’t published this yet, and he’s not ready to tell us because he needs to be 100 percent certain of what these antigens are, but I think the approach itself is really groundbreaking. It was published about a month ago for TB.

And he’s using the same approach with chronic fatigue. So that’s a very exciting development. And when he can finally confirm that, I think we’ll know more about chronic fatigue and certainly know more about the mechanism in those particular cases.

Eleanor Riley from the UK Biobank was at the meeting, again showing or trying to work across, you know, international connections. And really a wonderful resource that they’ve been collecting in concert with the National Health Service in the UK. Dr. Ian Lipkin presented some of the data that was recently published in April with his microbiome analysis. And I think the theme there again was he and others in the community are developing biomarkers to help us subdivide what we know is a complex clinical presentation.

And finally we had Jose Montoya from Stanford who has developed a way to look at the immunological characteristics of a chronic fatigue cohort that he runs actually at Stanford. And he’s actually able to subtype patients into more severe and less severe clinical types based on some of the immunology. And that data is again unpublished but he said he’s writing it up. And so we’re hoping to see it in press certainly in the coming months.

And I think it will be really exciting to start to see the results of some of this newfound push into this area. And that was really the goal of pulling these people together. So it’s a great start. And I think there was a lot of synergy and a lot of excitement about where the work is. And so with that I’ll turn it back to Walter.

Dr. Walter Koroshetz:   Okay, I think those are the updates from the folks here at NIH. And now we’d like to open up the lines to answer questions best we can.

Coordinator:  Thank you. We will now begin the question and answer session. If you would like to ask a question please press Star 1, unmute your phone and record your name clearly. Your name is required to introduce your question.

If you need to withdraw your question please press Star 2. Again to ask a question please press Star 1. It will take a few moments as questions come through. Please standby. The first question comes from Sonja Heller. Your line is open.

Sonja Heller-Irey: Hi there. My name is Sonja Heller-Irey. And I’d like to thank you Dr. Koroshetz for your public presentation today on the NIH’s efforts to advance research on ME/CFS. And before I ask my question, I’d like to share my background with you. And I apologize in advance, my heart rate monitor is going off because I’m a patient and even though I’m just lying here in my bed speaking to you, my heart rate is almost triple the resting heart rate because I’m expelling effort of speaking to you. So I apologize for the beeping in the background.

Before I ask my question I’d like to share my background with you. Before contracting ME/CFS I was a GS-15 U.S. foreign service officer in my 30s. I was stationed in Honduras. I was very happy, healthy and athletic. And I had a very successful career, a husband and three young children. At age 39 I contracted mononucleosis.

Within months I could no longer walk, speak, brush my teeth, bathe, watch TV or even sit up and eat unassisted. My cognitive function was also deeply impacted but I was keenly aware of the severity of my illness and immense suffering. The State Department evacuated me from Honduras to Washington D.C., where I saw some of the best doctors in the country and I was diagnosed with ME/CFS.

One of my doctors told my mother and me that I would be quote “better off dead”, because the medical field knew almost nothing about ME/CFS other than that there’s no treatment, no cure and almost no biomedical research being funded to fix that. The State Department immediately curtailed my job and my husband’s job, kicked my family out of Honduras and out of our home, my children who were six, eight, and ten were forced to leave their school, their friends and their community and a few days later my husband walked out on the four of us never returned.

Sonja Heller-Irey: With no one else to turn to for help, my elderly mother relocated across the country to care for my three children and me. However the strain of doing so caused a series of strokes the left her permanently paralyzed and confined to a nursing facility. I now pay a full-time caretaker for myself and my three children. Dr. Koroshetz, I wish I could convey the degree of devastation and trauma this disease has caused me, my three children and my extended family.

Today and every day for the past six years, I’ve been a living nightmare with little to no clinical care, medical treatment, support or hope of a cure. My own government’s refusal to adequately fund biomedical research on ME/CFS has converted me from a happy, healthy, social and active wife, mother and a prosperous and successful career woman into a barely functioning, fully disabled, single parent who struggles to survive and to support my three children on disability payments.

Obviously my health is slightly better now and that I’m able to speak with you today, but I’m still 85 percent bedbound and living with catastrophic disability. And it’s not just me. My story represents the millions of Americans with ME/CFS whose lives have been completely destroyed by our government’s decades long refusal to adequately fund biomedical research.

Given this context Dr. Koroshetz and the public statements from top ME researchers at Stanford, Columbia, Cornell, and other prestigious universities who are clamoring for ME/CFS funding and who have said that we can solve this disease in three to ten years with adequate resources, as well as the recently published paper by Dimmock, Mirin & Jason showing that ME/CFS should be receiving almost $200 million annually according to the NIH’s own DALY formula.

I’d like to know why the NIH continues, by your own public admission last month at the June 9 meeting of the Advisory Committee to the NIH Director, why do you so grossly underfund ME/CFS relative to other similarly or even less burdensome diseases? And given the two billion plus ups for each of fiscal years 2016 and 2017, what are your specific plans to correct this profound and discriminatory funding inequity within your own institute and within the other institutes that comprise the Trans-NIH ME/CFS Working Group? Thank you.

Dr. Walter Koroshetz:   So Sonja first to say, you know, the tragic story that you put out for us is, deeply motivating to the people here at NIH. But the hope is that this will also motivate investigators around the country, either who are interested in ME/CFS or maybe haven’t heard of it before but are drawn by the need to come into the field and bring in their expertise.

And so I, you know, we totally agree that the amount of funding for ME/CFS research is not even close to the burden of illness. I would say that at NINDS we have 400 diseases and no disease actually gets what they need. But ME/CFS certainly is in a condition where really big changes are needed. And that’s the reason for trying to set up this coordinated research program across the country. We really hope that this is going to make a big difference that NIH ME/CFS research went up from $6 million in 2015 to $8 million in 2016.

Sonja Heller-Irey: Excuse me I’m sorry to interrupt but that’s peanuts.

Dr. Walter Koroshetz:   Yes I know. I was going to say that the hope is that this is something that’s going to bring people in. At NIH the funding that goes to a disease is not based on any formula. The funding that goes to a disease is based on the applications that are submitted and get peer reviewed. And what we need in ME/CFS research is a large number of people to get into the field and to submit their applications.

And we need to train investigators. We need to get new people into the field. And I think the RFA starts that off. But as you said, it has got to be just the beginning because right now it’s peanuts.

Sonja Heller-Irey: I guess I appreciate that very much. I think I have two comments to that. The first is that it was wonderful to see how many strong researchers submitted proposals for the RFAs. And given that there were so many that were submitted I’m hopeful that maybe you can fund all of them if they were all strong.

And I guess my second point is since I’ve worked for the federal government I’m well aware that when something is identified as a political priority funding can be reallocated to it, resources can be ramped up exponentially, grants can be expedited, major programs can be put into place in a fraction of the time it normally takes. But this hasn’t happened with ME/CFS.

Dr. Walter Koroshetz:   Well I think I disagree with you there. The Intramural Research Program was an example of that and the RFA is an example of that. There are many diseases that have no RFAs at all. So I understand that this is a disappointing state of affairs and we agree with you, but to actually do this in the right fashion we have to instigate a major effort to get more people in and see how the investigators respond to that. So I think we should go on to the next question please.

Sonja Heller-Irey: Thank you.

Coordinator: The next question comes from Leonard Jason. Your line is open.

Leonard Jason:  Thank you. Yes I had a couple questions, you know, one is again I appreciate the information about the internal research program and also about the RFA. The one that was done about a decade ago did really stimulate a lot of good research and, you know, hopefully this one will too. So one question is, you know, given the work that’s going on and certainly Vicky has been a champion as well as others to kind of really push this, can you help us understand kind of the change that has occurred within the last couple of years? Maybe a little bit about the, you know, the reason for the more interest and the more focus and all of the things that you’ve been talking about on this phone call?

And then the second issue which is more kind of a warning and maybe might be more hard or maybe not even possible to answer, you know, there’s been indications to the scientific community that there may be a reduction in funding at NIH in the future based on some comments from our Chief Executive in the White House. And I’m just wondering if that were to occur, how that might affect some of the plans that are being initiated? And I recognize this is certainly a question that might not be able to be answered. Thank you.

Dr. Walter Koroshetz:   So I’d just start off by saying that, you know, I think the changes that are have occurred that I’ve seen, and this is a biased view I’m sure, is that technologies are becoming available that can be focused on the problem of ME/CFS research and they were not here before. So the microbiome work is one example. The detailed immunological phenotyping is another example. If you look at science what will attract people into a field?

One is the devotion to the patient. And so the bond between the physician and the patient is often what pushes the physician scientists to really make a commitment for a career in research to try and do things better. Similarly, the laboratory scientists are oftentimes affected very profoundly by their interaction with patients or patient advocacy groups. And this can hook someone to bring their research into a field where they feel they can make a very large impact. I think most people go into science because they want to make an impact on health. But I think the more that happens in this vein, I think that will help bring more people into the field. But there’s nothing like a technology that allows you to explore things that they couldn’t explore before.

And I think also I’m very hopeful that an organized approach to ME/CFS will establish a foothold of resources of expertise that can kind of spread throughout many of our very good research centers across the country and bring young people into the field that otherwise, you know, would not have thought about entering the ME/CFS field because the need is great but people need to see a path forward.

And since it’s been such a mysterious disease I think that’s held some people back. So I think that the coordinated approaches, the new technologies and the continued work by the patients and the patient advocacy groups to cultivate and spread the opportunities and the need as well to research is really what’s going to make the difference and get us to solutions to what, you know, as Sonja said is a horribly tragic problem and with very little clues as to how to proceed.

So I think we have to prepare for the long haul here. We could get lucky I’m sure. It would be awesome if we could get lucky and get some quick strikes that would help people quickly. But I suspect that this is going to be a tough problem that’s going to require a real massive effort on behalf of a lot of really smart scientists to get at the bottom of this working with patients. Can we have the next question please?

Coordinator: The next question comes from Eileen Holderman. Your line is open.

Eileen Holderman: Yes, good afternoon. I’m Eileen Holderman. I’m an advocate and I formerly served on the CFS Advisory Committee for four years. My question is to, is it Dr. Green? I didn’t get the name. I’m sorry about that. Is it Green?

Marian Emr: It’s Dr. Breen.

Dr. Walter Koroshetz: Dr. Breen is from NIAID.

Eileen Holderman: Dr. Breen. Oh, okay, I’m sorry. Okay so I noticed Dr. Breen was and I don’t want to just single him out, because many people do this, kept using the term chronic fatigue. And there is a condition with an ICD code for chronic fatigue. It’s a condition of common tiredness due to overwork or many other such things.

And it has no relation to ME or what some people call chronic fatigue syndrome. So that’s very concerning because advocates mounted a protest against the NIH Intramural Study because it was first announced that the Reeves criteria was being used, which is basically recruiting patients for chronic fatigue - the condition, not the disease.

And then as many of us mentioned the NIH changed six times what the criteria was going to be, finally settling on the CCC, the Canadian Consensus Criteria. So my question is does everyone at NIH clearly understand how important it is to differentiate between the disease and the condition of CF and to use the proper terminology? And can you reassure us all on this call today that the NIH Intramural Study and all studies that NIH and all programs at NIH are indeed using the experts’ criteria which is the CCC, Canadian Consensus Criteria and the ME ICC International Consensus Criteria? Thank you.

Dr. Walter Koroshetz:   Yes, thanks for that and sorry for the confusion. Yes NIH is particularly is focused on the disease of ME/CFS and not the condition of chronic fatigue that occurs in various other diseases and disorders for this purpose. I mean certainly there’s a lot of research in cancer and multiple sclerosis that’s looking at fatigue itself. And that might be very helpful to us as well studying ME/CFS. But for the purposes of this focused program we have now is on the disease. And maybe I’ll just let Avi talk about the criteria that we’re using to bring patients in to the study at Intramural.

Dr. Avindra Nath: Yes, so you’re right. We’re not using the Reeves criteria any longer. We have a panel of experts who are going to look at each of these patients, make sure they meet all the CCC and the criteria to properly diagnose these patients. And from the get-go we had actually had, I had put a lot of effort to make sure we get the right type of patients, always understood the difference between chronic fatigue and ME/CFS. And in fact, all patients have to have a variety of criteria that they have to fulfill. And I think we’ve been through this many times over, but I’m absolutely certain beyond any element of doubt that we will be recruiting the right patients for the study.

Eileen Holderman: I appreciate that Dr. Nath. And I think it would be helpful to the patient community and stakeholders that so that we don’t have to keep asking that question, so that all the investigators and the NIH people use the right terminology so it doesn’t then, you know, cause ...

Dr. Avindra Nath: Well if somebody uses the wrong terminology, I can’t police anybody. But I can tell you as far as our study is concerned that absolutely we have no element of doubt it will be the right study the right patient we recruited to it.

Eileen Holderman: Right, not policed but just to educate. Thanks again very much for explaining that.

Dr. Walter Koroshetz: Thank you. Okay on to the next question please.

Coordinator: The next question comes from Nancy Klimas. Your line is open.

Nancy Klimas:  Hi thanks. This is Nancy Klimas, just two quick points. One is just historically this is very interesting that the two times we’ve had really excellent responses to call for proposals have been when there has been an announced set-aside intent to fund. So that’s interesting because it suggests there’s a skepticism among the investigator community still to this day despite all the changes that have been made that they will have difficulty finding funding if they go down this path. But when it was in the Office of Research on Women’s Health there was one set aside where they received several dozen proposals when they were normally receiving only two or three in a round. I thought that was interesting. There was only $3 million set aside that people really responded to that.

And then this last round when the centers awards you received, you know, ten applications apparently for that, and that’s fantastic. I mean that’s really outstanding. So I would suggest, if there’s a chance to suggest something, that since we need to move from the basic sciences into clinical trials somehow that you might consider a set aside round for a call for proposals for a clinical trials network or a clinical trials program of some sort to move some of the advances in our knowledge forward into actual treatments. As you know right now it’s very, very difficult. And I don’t know of any current studies underway that are NIH funded that are moving the knowledge forward into trials. Thank you.

Dr. Walter Koroshetz:   Thanks Nancy I mean that certainly is a goal that, you know, the research only comes to fruition when it comes goes into clinical trials that helps people. And so I think that that’s something that we definitely have our eye on going forward, so thanks for that.

Nancy Klimas:  Thank you.

Dr. Walter Koroshetz:   Next question please.

Coordinator: The next question comes from Wilhelmina Jenkins. Your line is open.

Wilhelmina Jenkins: Thank you. I wanted to ask about the possibility of additional RFAs or similar kinds of programs to supplement what’s already going forward? I think we all appreciate the importance of building a network with the RFAs already issued. But I think we also all listened to Dr. Lipkin speaking with you Dr. Koroshetz and talking about the fact that the amount of money in the RFAs was painfully low in order to accomplish what they wanted to accomplish.

I wonder if there’s any possibility of increasing the money to those RFAs or having additional RFAs particularly devoted to areas of interest in research that are coming out now? My first thoughts are the rituximab studies that are coming out soon if there’s a possibility of having an RFA for studies related to the B cells that are identified in the rituximab studies or if there could be an RFA related to metabolomics? Those areas seem to be exciting areas at the moment. And we need to pull people in as quickly as possible. They could hook into the already existing network of course. But is there a possibility of additional RFAs coming out for ME/CFS?

Dr. Walter Koroshetz:   I think that those - that all these things we’re looking for is to see what we can do to stimulate research. And so, you know, going forward I think the group will be looking at other avenues as we go forward. There’s also, we had a program of supplementing grants that were either in the ME/CFS space or a slightly related area. And I think we got pretty good submission pressure for those as well. I don’t know if Joe wanted to mention...

Dr. Joseph Breen: Actually the Davis work that I mentioned before was supported directly by one of those supplements. Those were - actually they’re ending about now. They were one year awards. There was almost $1 million between NINDS and NIAID, ten one-year awards.

Dr. Walter Koroshetz:   And then in terms of the others, there are mechanisms, you know a clinical trial is a, and Nancy also brought this up. A clinical trial at NIH is always a major undertaking because it’s putting people through procedures that may actually be risky. You never know what the final outcomes are going to be.

But all the institutes have a particular mechanism whereby they review and run clinical trials. The bar is certainly higher because of the risk and also the expense of a clinical trial. But these are all, what we’ve seen in the past is when groups have organized become sophisticated scientifically what we’ve seen is that they’ve become successful at running trials and getting funded based on their past history, funding the next trial and that’s what we really would like to see in ME/CFS. And I think the RFA we have out now for the coordinating centers I’m hoping that, you know, that this group will be very successful and will be the group that is kind of the nucleus maybe to either themselves or work with others to submit the clinical trials or other type of research.

Wilhelmina Jenkins:     I wasn’t wondering about clinical trials because Dr. Klimas had already discussed that. I was really wondering more about the basic research, the rituximab research indicates more basic research needs to be done in terms of the mechanisms that make that a successful drug for some people with ME/CFS. And the same for metabolomics, its basic research that needs to be done. RFAs seem like the best way to pull people into those fields. Would that be possible?

Dr. Walter Koroshetz:   Yes. I think if we see an opportunity there, those are the kind of things that the group would think about. But people are always free to submit a grant. People often think that there’s a requirement at NIH for an RFA to be available to submit a grant. We just went over our data today and basically 60% of our budget goes to R01s that don’t come in to an RFA at all, so most of the NIH money is not a response to RFAs. But you’re right, that when you need to stimulate a field that’s the best way to do it.

Wilhelmina Jenkins: We certainly hope that happens. Thank you.

Dr. Walter Koroshetz: Thank you so much Wilhelmina. Yes next question?

Coordinator: Next question comes from Betsy Keller. Your line is open.

Betsy Keller: Hi. Thank you very much for entertaining this forum. I think it’s really important to have these discussions. And I’d like to follow-up with Nancy’s comment not so much about clinical trials but also that of the last caller about RFAs. And Dr. Koroshetz you talked about the organized approach. The Common Data Elements Project here is helping to try to support that. You talked about the advent of new technologies that might help us, you know, to further our understanding of this illness and perhaps bring new people into the field because it is a complex disease.

I have done the two- day cardiopulmonary exercise test on more than 120 patients. And I kind of take an alternative viewpoint. I see the commonalities in the illness after having tested these patients. And I think that while it’s complex because we don’t understand it and it’s complex because largely physicians don’t have much background with it therefore don’t know how to look at the illness from a clinical perspective, physicians at large, that it’s off- putting from that perspective to study it. However those of us in the ME/CFS research community probably all have experiences with potential young investigators who have been put off by the field because it is so difficult to get funding when you have a funding level of 11 percent, or less in some cases, and you’re up against, you know, all of the other proposals that are going into NINDS or whatever.

So again I guess I would advocate strongly for an RFA to study this illness so that we will attract new people who are very hesitant to put their new, young careers at risk for a field that is traditionally hard to get funding for. And with the five, we can argue how many millions of dollars per year has been put forward towards this illness, but relatively speaking it’s a very small.

And our first patient, you know, presented to you and the rest of us a story that is very common for me because I’ve heard it over and over and over again. And it’s tragic. And, you know, every time funding for a proposal is passed by, I think about these patients that are sitting there not being treated even for their symptoms, let alone the disease. And so I guess I’m far less patient than most people but I think it’s long overdue that we have RFAs specifically to understand and study this illness. And I don’t think that waiting for people to propose to a field that’s traditionally been underfunded and difficult to move into is going to bring the new investigators into this field.

Dr. Walter Koroshetz:   Well I think, again I agree. I agree totally that this field needs a greater incentive to get people in. I’d say the other thing, you know, that if we have a national coordinating center, that really elevates it to a new level. I think, you know, just off the bat trying to think of the other diseases at NINDS that have anything similar. Maybe four, five other diseases out of the 400 have something like that. So I think that elevates it.

I think the other thing is that much of the research in ME/CFS was done on small groups. And the sample size was often limited, limiting the ability to generalize about the illness, so setting up a data coordinating center for the consortium, they can bring data in from multiple projects and actually then say test things that look like they may be promising in a coordinated fashion. I think that’s the other thing we’re thinking, that the centers that we’re setting up may have a lot more impact over the long run in addition to the funding that they’re getting that they can help leverage the grants that other people are putting in, to get behind their efforts to bring in and their data and clinical coordinating infrastructure to help other researchers. I think that’s also something that we’d be looking for these centers to do.

Betsy Keller: Well I appreciate that. But I do know as one who served on the IOM Committee that put out the report in 2015 along with Nancy and probably several other listeners here that that was a major finding of our review that there are many actually somewhat promising studies that have been conducted that were never repeated, presumably and more likely because of lack of funding to repeat these studies. So, you know, we do have some knowledge. We just haven’t been able to reproduce the studies and, you know there is a key issue with that. So hopefully again RFAs are going to be really, really important to be able to follow-up on some of the things that we think we might already know about this.

Dr. Walter Koroshetz:   Yes. And I think also to doing the coordinated way and going forward is also going to be a big help.

Betsy Keller: Thank you.

Dr. Walter Koroshetz: Okay. Can we go on to the next question please?

Coordinator: The next question comes from Donna Pearson. Your line is open.

Donna Pearson: Hi there. Thank you so much. I need to jump on the RFA bandwagon as well. But I have a slightly different take on where we should first put our money. I think we need objective diagnostic testing of some type. I think once that happens, doctors will start to pay attention, research will certainly start to pay attention and news will get out that, yes in fact this is a real disease. I think that most people in the medical community are still not convinced, I’m sure you that you all agree with that, that this is a real disease. And even though we’re going to have coordinated centers that doesn’t necessarily mean that that that will convince people that it’s a biological disease. And I ask you, I believe that at the end of the fiscal year you might look at your leftover funds sometimes and decide if you can put any of that money to anything and, you know, any pet projects that you might have. And if that’s the case, I wonder if you could please prioritize RFAs for this disease.

Dr. Walter Koroshetz:   Thanks very much, Donna. Yes I think everyone in the field is very much focused on the need to be able to develop objective diagnostic measures that will help either diagnose the disease but probably, maybe more importantly, enable the segregation of the subsets of folks who have ME/CFS because as was mentioned one of the other previous comments is that from what we’re seeing now the likelihood of everyone responding to a certain medication is fairly low but there may be subgroups that can identify them and focus on them we may have better success. Avi do you want to mention anything about this issue of the diagnostic...

Dr. Avindra Nath: I do yes.

Dr. Walter Koroshetz:...besides the clinical criteria but, especially biological diagnostic types.

Dr. Avindra Nath: So Dr. Koroshetz is absolutely right no matter if you have clinical criteria for any disease it is somewhat dependent upon the patients providing you the information and the clinician, you know, interpreting it. And so there’s always going to be drawbacks and flaws in that way of being able to diagnose diseases. So Donna brings up an important point that what you really need is objective criteria. You know, an example is if your hemoglobin is low, nobody will question that you have anemia even though you may not know what the cause of it might be, right?

So I think our study particularly is very focused on trying to determine this. In an unbiased manner, we are looking at a wide variety of biological markers. We’re throwing every known sophisticated technology at these patients to see if we can identify a subgroup that will have, you know, dysfunction. And we’ve targeted a subgroup of ME/CFS patients that have a clear episode of infection and then there was the syndrome. And so that way we hope we can get as close to a homogeneous population as we can so we can identify something that would be there. There’s brain connectivity, so you have MRI related techniques that we’ll look at called functional MRI. If it’s an immune-mediated phenomenon, we should be able to pick it up in the spinal fluid or the blood and so on and so forth.

If it’s a mitochondrial dysfunction, we’ll pick it up again in blood cells that are challenged for mitochondrial function. We’ll be looking at muscle tissue to make sure there isn’t something there. If there are genetic correlating factors we should be able to find those as well. So our hope is that we will be able to come up with a set of objective criteria at the end of this so that they can then be validated in larger cohorts. But even if we come up with something, that may not be the end-all. It still has to be validated in other cohorts across other centers before you can come up with a solid criteria.

Dr. Walter Koroshetz:   Thank you. Can we go on to the next question?

Coordinator: The next question comes from Loetta Vann. Your line is open.

Loetta Vann:    Hi. Actually my point was going to be addressing the same thing that Eileen Holderman spoke of. And I would not be able to do it as succinctly or elegantly as she did. I would like to add to her comments though the importance of the use of terminology, as the information is going from NIH and the bench out to clinical practice. I’ve been dealing with this illness for going on 32 years now. And it’s really important then, out in the neighborhood, that the doctors know the difference between chronic fatigue and chronic fatigue syndrome. And I’m wondering if maybe it is appropriate to have a terminology policeman out there looking at some of the printed information that’s being distributed. That’s all I have.

Dr. Walter Koroshetz:   Okay thanks very much, Loetta. We have another question then?

Coordinator: The next question comes from Jesse Kramer. Your line is open.

Jesse Kramer:   Hello. Yes I’m a patient and I’m calling to piggyback on the last question about biomarkers. There’s been a long history of research that’s gone into enteroviruses as a trigger and potentially an ongoing cause. Some of that work’s being done now by John Chia in Los Angeles as well as Byron Hyde in Ottawa. And I just want to make sure the NIH is aware of that research and that they’re looking into that as a potential biomarker and as a target for both vaccines and treatment and that they’re also aware that these viruses, after the acute phase, tend to show up in stomach tissue, in brain tissue and heart and are not always able to be found in blood. Thank you.

Dr. Walter Koroshetz:   Thanks very much. Yes I think viruses as a cause may be continuous contributors and something a lot of people have been looking at. And Dr. Nath is actually, his expertise is in neurovirology. And so that’s certainly an area that he’s very interested in. And so yes we’ll keep those clearly at the top of the list.

And Dr. Breen is from the Institute for Infectious Diseases here at NIH. So that’s what has brought NIAID to the table as well, along with the autoimmune aspects of ME/CFS, potential aspects, of ME/CFS. So yes we have lots of areas to look at, the microbiome, autoimmunity, response to infection. And I think we have to pursue all these avenues right now because we don’t have a clear winner there. I don’t know if Joe or Avi wanted to mention something there.

Dr. Avindra Nath: So specifically for enteroviruses as, you know, somebody had mentioned earlier about mononucleosis, which is EBV so there are a lot of infections that have been associated with ME/CFS. So, I don’t want to bias ourselves but we’re collecting every tissue that we can and we’ll look at any signature of exogenous and even endogenous viruses. We haven’t talked about those, but that may activated in patients.

And so technology now allows us to look at these things in an unbiased manner so we don’t have to particularly look for a virus because then the likelihood is you can miss the others and there could be related ones there. So yes if this there is an enterovirus to be found, I think we will find it now. Now we’re very aware of the literature and very familiar with the family of enteroviruses ourselves.

Dr. Joseph Breen: Yes I’ll just say that the, you know, NIAID supported work in the connection between potential viral etiology for chronic fatigue for chronic fatigue and ME/CFS for a long time actually and will continue. Those we do have had - we’ve had steady support. So we’ve had a number of grants that have come in with the regular R01 group and have gotten support through peer review. I would imagine we continue to do so because the connection, the post infectious connection is still there, which is why NIAID really part of this discussion and part of this effort but we don’t understand it. But that’s what drives us to keep going.

Dr. Walter Koroshetz:   I would just end by just going I guess back to what I was pushing in the beginning is that you mentioned that the virus may not be in the blood but may be in the brain. That gets back to this issue of really needing brain tissue to examine because the, I don’t actually know of any exhaustive or even, you know, even minimally comprehensive look at brain tissue and ME/CFS with regards to dorsal root ganglion and ME/CFS with spinal cord. So we have no idea what’s going on in the central nervous system about access to tissue at some point. It’s a delicate matter but the groups like the Brain Donor Project that Tish Hevel runs and NIH NeuroBioBank trying to get tissue that investigators intend to use and examine it’s one of the things that brings people to the ME/CFS field, if there is available resources.

So with that I’d like to really thank everyone for their questions and the good discussion and clearly the overriding point was that we need more money and that no one’s disagreeing. And I hope that we can, one of the successes of the new initiatives here will be that each year we see a rise in the amount of funding that goes to ME/CFS until we actually get a treatment that works for people.

And that’s our goal. I appreciate everyone’s work out there because I think it’s a shared goal. And success is really dependent upon a coordinated approach by not only NIH and its investigators but also by the people on the phone and the advocacy groups that represent the patients. So I want to thank everyone for their remarks and questions.

Marian Emr: So in closing today’s call I’d like to remind you that a recording and a transcript of the call will be posted on the NIH ME/CFS website next week. I’d also like to remind you about our listserv for updates from NIH. If you received a message about today’s call then you are on our mailing list already. If you received a notice from a friend but would like to be added to the listserv, please visit the NIH ME/CFS website and click on “Join our listserv” at the bottom of the left sidebar. Thank you and good afternoon.

Coordinator: That concludes today’s conference. Thank you for participating. You may disconnect at this time. Speakers please allow a moment of silence and stand by for your post-conference.

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