On Tuesday, March 8th, NIH held a one hour tele-briefing to answer the community’s questions about their plans for the intramural study and the ME/CFS program. What follows is a full transcript of the conference call.
You can view the transcript and listen to the audio of the call on the NIH website.
On the call were NIH Director Dr. Francis Collins, Dr. Walter Koroshetz, Dr. Avindra Nath, Dr. Brian Walitt and Dr. Vicky Whittemore. The NIH plans to release the full recording of this discussion on their website at a later date.
Moderator: Welcome and thank you for standing by. At this time all participants will be in the listen only mode until the question and answer session of today’s conference. At that time, to ask a question over the phone lines,please press star1 and record your name at the prompt. This call is being recorded. If you have any objections, please disconnect at the time.
I would now like to turn the call over to your host, Marian Emr, you may begin.
Ms. Emr: Good morning, This is Marion Emr. On behalf of the NIH, I’d like to welcome you to this morning’s teleconference, and to thank you for your great interest in participating in this discussion with us today. Here at the table this morning we have Dr. Francis Collins, Dr. Walter Koroshetz, who will introduce Dr. Vicky Whittemore and Dr. Avindra Nath, and Dr. Brian Walitt. Each will make very brief opening remarks and then we’ll open the phone calls for your questions. Please be patient with us through this process; we will try to get to as many questions as we can in the time we have available to us this morning. Now, Dr. Collins.
Dr. Collins: Thanks. Good morning, everyone. I wanted personally to join this call, to thank you for joining us for what I hope is an ongoing conversation about ME/CFS and how we can move the needle forward together on characterizing the cause of this perplexing disorder to help with better diagnosis and treatment. I want to assure you that from the perspective of the NIH Director that this institution is very committed to this area of research. Speaking for many of us, we want to uh, eh, move the research agenda forward here, both in terms of intramural activities which you’ll be hearing about and extramural research programs as well.
Uh, happy to tell you that with regard to the intramural effort, we have received IRB, that’s Institutional Review Board, approval, and expect to be able to launch this study at the NIH Clinical Center and begin to enroll individuals this summer. I have great confidence in Avi Nath, who is the Principal Investigator who’s going to speak to you here shortly, who will lead this important study and he can tell you more about it. A website describing the intramural protocol actually went up up this morning. If you haven’t seen it yet, this will give you a lot of details about the design of the study and how it’s gonna be conducted. And I think this is a remarkable opportunity to try to bring the full power of this really remarkably interdisciplinary research hospital to bear on this set of serious questions about what are the causes of ME/CFS.
There is a lot of heterogeneity, of course, in this condition. The choice here was to focus on individuals who had previously good health and then a clear-cut onset in the context of a flu-like illness in order to limit the heterogeneity and provide us with a better opportunity for getting answers and we believe that this study in the world-class Clinical Center of NIH has the opportunity to provide some new insights that could be transformative for all of those who suffer from this condition. So, in addition, on the extramural side, a vigorous reinvigorated trans-NIH Working Group is working to divine the strategic areas of research that would form the basis for a Request for Applications to the extramural community, both in the short term and in the longer term, and Dr. Koroshetz can tell you more about where we are about that particular set of discussions. We’re quite serious about looking for opportunities to expand our research in this area and to recruit new investigators in the field, bringing new eyes and new brains into the issue of trying to understand the puzzling aspects that previously have eluded us.
So, please take our commitment with great seriousness and please also stay the course with us as we seek to identify the most compelling research questions and how we can address those . Uh, I understand many of you have waited a long time, perhaps, to see this kind of attention. I hope you understand how much we are now looking at this in a very serious way and seeking to come up with some of those answers. So, if we can work together on that, and not work apart, I think we have a much better chance of making real progress. We are your partners. We want to hear from you, that’s why we’re having this call today. And we’re listening carefully to the comments and suggestions you might have about how best to move this effort forward. So, that’s mostly what I wanted to say, by way of introducing the call.
I now want to turn this over to Dr. Walter Koroshetz, who as you know is the Director of National Institute of Neurological Disorders and Stroke. Walter is a neurologist, a very experienced one, and he has seen first hand how devastating ME/CFS can be for patients, and he volunteered to chair this trans-NIH Working Group and is working closely with other Institute and Center Directors to promote research on ME/CFS and I want to say thank you to Walter for stepping into this space and already with considerable vision, figuring out ways that we can make the kind of scientific contributions this field very much needs.
Walter, the floor is yours.
Dr. Koroshetz: Thank you so much Francis, and again I’d like to thank everyone for getting on and I’d like to thank everyone for the expressions of interest and even the concerns that people have, have sent to us. We are very interested in working together with the community uh to achieve our long term common goal, and I think that common goal is shared unanimously, which is to find better treatments for people who are suffering with ME/CFS and I can just like to start off by talking about the big picture, uh, the intramural research protocol, I think, is one step, but only one step, in the trajectory that we need to get on to get answers that are gonna be very helpful for patients. And, so, this is, I think, a long term quest, uh, this is a difficult problem. I think if it was not difficult it would have been solved long ago. Uh, so I think we need to um kind of get out there and and bring in the best and the brightest uh from many different areas of science. I don’t think we know where the solution is going to come from. So I think we need to cast a wide net, uh, get involved a number of very experienced researchers and clinicians and work carefully with the doctors who are taking care of the patients. So we, as Francis said, I think the important thing is to stay the course and to look always to the long term goal.
At NIH, uh, we have some bureaucracy which is not easy to understand, but I’d like to simplify it if I could, but there is basically an extramural program and the extramural program funds that , you know, go from the NIH out to universities, companies, other institutions to do research, and there’s the intramural program where research is done at the Clinical Center at in the Bethesda area. The Clinical Center is the world’s largest research hospital, and really our only research hospital, has tremendous resources, but 90% of the funds from NIH go out to the extramural community. So, in the long run, what we need to do is to engage both the extramural and the intramural community and you’ll hear about the intramural protocol which is starting up but you also heard mention from Dr. Collins that we have a trans-NIH Working Group. Uh, as I mentioned, we don’t know where the solution for this ME/CFS problem is going to come from, so it’s very important to have the scientific input and the funding resources of multiple Institutes at NIH to bring them to bear on this problem. The trans-NIH Working Group has representatives from all the Institutes and is working to develop plans that will move funds to very worthwhile, highly meritorious research proposals in the extramural community. And we have the intramural protocol which is gonna be run by Dr. Nath.
With that, I’d like Vicky Whittemore to briefly describe the trans-NIH Working Group and what it is about and and thinking of doing in the short term and the long term. Vicky?
Dr. Whittemore: Good morning. This is Vicky Whittemore, and I’m a Program Director at the National Institutes of Neurological Disorders and Stroke and I also would like to thank all of you for being on the call this morning. I’ve been working with Dr. Koroshetz to coordinate the trans-NIH Working Group, and I have to say, it’s really been a pleasure working with representatives from the staff of the 23 Institutes and Centers who make up the Working Group. Everyone’s really dedicated and passionate about what we’re doing and about what we’re working on. Um, we are in the process of putting together, as Walter said, both a short term plan, where we can try to activate some research on the shorter term, as well as initiatives that would put in place better infrastructure as well as research funding for longer term research projects and some of the things we’ve been talking about clearly, as the community has communicated to us as well, the priorities of developing and identifying biomarkers for the disease, really understanding the underlying causes and mechanisms that lead to ME/CFS, as well as getting a handle on and understanding what is causing what patients refer to as brain fog, or the cognitive symptoms that many individuals with ME/CFS experience.
So, our timeline is that we’re working very hard to put this plan in place, um, and to present our initiatives to the appropriate councils for approval in the May time frame and we will be able to move forward with initiatives soon after that.
So, we will be looking for input and feedback from the community and I think several ways that we’re thinking about doing that is to put out specific requests to the community for feedback on ideas we have and things we’re thinking about, to have additional follow-up conference calls after this one in due time, as well as to reach out to the research and clinical community to get feedback from them as well in terms of what we’re thinking and planning. So with that, I’ll turn it back over to Dr. Koroshetz.
Dr. Koroshetz: So, I just wanna clarify one thing, because I’m sure people are wondering out there, uh, why can’t we actually say what we’re thinking? Uh, and so it is important to understand that NIH has processes that ensure that research comes in and the most highly meritorious research is funded and that all groups have a fair hearing when they come in. So what we can’t do is, we can’t put information out that would give- before it’s ready to be made public to everyone. So, that’s where we have to do a lot of work behind the scenes, uh, before we can make things public, so it’s a kind of something that’s idiosyncratic but it has its real purpose in presenting a fair and open process here at NIH.
And, now, I’d like to say also that, as I mentioned before, I think it’s gonna take an army of really good researchers to solve this problem. Uh, I think that army has to work together.
It can’t be individual groups working in isolation so what we’d like to do is to form a consortia, really, of investigators who are working hand-in-step, not all doing the same thing, but allowing a lot of innovation, and the first, uh, horse out of the gate is the intramural program, so I would like Dr. Nath, if he could, to try and briefly describe what the intramural protocol is all about. And I would say that Dr. Nath is calling in from Liberia, where he’s doing field work in Ebola, and, uh, so, we’re very gratified that Avi can get on the call, and we hope that his line stays stays stable from Africa. Uh, Avi, would you like to describe the intramural…..
Dr. Nath: Ah, thank you very much, Walter. This line should be fine because I’m using one at the US embassy.
Dr. Koroshetz: OK, good.
Dr. Nath: So, uh, well, thank you very much. So, you know, I’m delighted to be the Principal Investigator of the intramural study. And when Dr. Collins and Dr. Koroshetz asked me to consider this responsibility, I was actually very thrilled to be able to look at the syndrome and see, uh, if there is a immune or neuroimmune component here that may be driving the disease. That is an area of my expertise. I have first hand seen a lot of patients with the disease and know exactly how devastating it can be. And, so when I looked at the literature, uh, it was very clear to me that there are very good reasons to believe that this is likely immune-mediated and so I designed a protocol that would address those kinds of issues.
So, the proposal I put together has three phases to it. Um, the first phase is a cross-sectional study and that’s the protocol that’s on the web and all the information that many of the groups have received. However, it is in the plans our second phase study. Second phase study would be a longitudinal study, which will follow patients over a period of time with repeated testing but only with a small subset. The first phase study has a lot of various kinds of investigations we will do, and then we’ll identify the ones from there that look most promising and then in the second phase study, a very much larger population, different types of populations, and then be able to study them over a longer period of time.
And then the third phase would be an intervention study, so based on the information that we gather from the first and second phase, that will guide us as to what kind of immunomodulatory therapy would have the best opportunity of making a difference in this patient population.
So, uh, that in summary is what we were thinking about as our goal towards developing a research protocol for Chronic Fatigue Syndrome.
Dr Koroshetz: Thank you very much, Avi. Can you still hear us all right? [Pause]
So now I think I’d like to turn to Brian Walitt, who’s a medical officer at the National Institute of Nursing Research. He’s had considerable clinical and research experience in fibromyalgia and ME/CFS research and he will serve as a lead associate investigator to help Dr Nath coordinate the activity of a large number of investigators who will be involved in the study at the clinical centre. So, Brian, do you want to tell us a little bit about what brought you to this really interesting protocol?
Dr Koroshetz: Thank you very much, Avi. Can you still hear us all right? [Pause] So now I think I’d like to turn to Brian Walitt, who’s a medical officer at the National Institute of Nursing Research. He’s had considerable clinical and research experience in fibromyalgia and ME/CFS research and he will serve as a lead associate investigator to help Dr Nath co-ordinate the activity of a large number of investigators who will be involved in the study at the Clinical Center.So, Brian, do you want to tell us a little bit about what brought you to this really interesting protocol?
Dr Walitt: Sure. Thank you, Walter.
Hi, I’m Brian Walitt. I am the lead associate investigator for the intramural protocol here at the NIH.
My experience with all of this starts as my career in Rheumatology, where I had a lot of experience with hospital immune disorders and developed a specialization in fibromyalgia and myalgic encephalomyelitis / chronic fatigue syndrome.
My interest in the disorders grew over time and led me to open a research clinic at Georgetown University where I saw patients on a regular basis. My patients taught me just how real these disorders are. They are not just in one’s head. They do not reflect some unconscious choice and it is not possible to simply push through the symptoms.
I tried my best to help my patients and learned just how limited the options really are and why there is an urgent need for a restorative treatment, one that would give patients their lives back. I promised my patients I would do my best to find better answers for them. This passion is what led me to come and work at the NIH.
Since I’ve been here are the NIH, I’ve been learning the ways that research is done here, I’ve learned a great deal about science from the world class scientists I get to rub elbows with. I’m very lucky in that regard. I am very excited to help Avi Nath facilitate the protocol. I believe it’s going to provide some important answers to the big questions of ME/CFS; the role of infection, the role of immunity and the role of neurology in the generation and perpetuation of symptoms. We’re also going to try to understand exactly what the biology of post exertional malaise is and I believe this will move the needle forward as Dr Collins said and I’m very excited to be part of this.
Dr Koroshetz: Thanks very much, Brian.
So I also just emphasize that the protocol at NIH has 26 associate investigators in addition to Brian and Avi and they bring this really incredible expertise to the table in the study of the patients with ME/CFS in this protocol and this ranges from very high level neuroimaging to high level ability to look at cytokines, autoantibodies, and we have people like Leo Saligan in the Nursing Institute as well who has been looking at chronic fatigue in patients with cancer and rheumatologic disorders. So we have a really quite amazing group here, different to what you might see in a hospital.
Everyone here is full time devoted to research. And so the community of research is quite extraordinary and also the tools that we have in the clinical centre are quite extraordinary. It’s very difficult to bring a patient in who’s very ill for research at a hospital any longer but here we have an in-patient unit where we can study patients over multiple days even weeks.
So we’re hoping that the resources of the clinical centre will allow us to do some very unique things but I would also emphasize once again that this is a stepping stone. This is only one piece of the puzzle. I think it’s a very important piece but our intention is to coordinate it with many of the other pieces that we’re going to start initiating across the country.
And with that I’d like to open the phone to questions now and we’ll do our best to answer them and once again if we don’t… are not able to answer all the questions, they can be directed to a website firstname.lastname@example.org. So thank you very much and let’s open the line.
Robert Miller: Hi, good morning, everyone. This is Robert Miller. I’m a long time patient and advocate. First, I’d like to thank Dr Collins, Dr Koroshetz and team for taking this key first step in doing the clinical centre study [inaudible] ME/CS. I think it’s a long time coming for this patient population but I’d like to start off and address possible treatments and, in particular, the treatment ampligen and I’d like to ask what homework has been done thus far regarding ampligen and if there’s been any talk with the FDA as this is the only treatment ever to be in Phase III trials for ME/CFS. That opening for this drug potentially could lead to this drug being our.. this patient population’s AZT, you know opening the door to [inaudible] for much more research. Most importantly it would give relief to many suffering patients. Thank you.
Dr Koroshetz: Thank you, Mr Miller.
You know, indeed, as I mentioned, the goal that we’re all marching towards is to try and get a treatment and clearly you…. to start off, I think we are going to challenge our investigators to survey the area of therapeutics that have been tried in ME/CFS, others that might have been tried in other illnesses that might come into ME/CFS ’cause those are more of the short term win, should they be effective.
Developing new therapies is you know basically [inaudible] to a longer process. So that is very important. So we certainly at the NIH have an open door policy for people to come in and propose research and we have certainly met with many investigators and even Hemispherx company people and they presented the data that they had from their previous studies. So that certainly is something that we are taking into serious consideration.
As I mentioned earlier, there’s a process at NIH for funds to go out so the process is again a peer review process where investigators submit proposals, they get looked at by the leadership and then they go out to a peer review system and they kind of poke holes to make sure that the best proposals get the funding for the American taxpayers. So that’s the system that would have to be engaged. Very different from an industry system where industry makes a decision to put the funds down and they take all the risks. Here we are working with taxpayers dollars and so the process is very important to uphold but certainly we are looking at that and we expect that we’ll be having discussions on clinical trials as they come forward.
So thanks very much for that question.
Dr Koroshetz (continuing): … But certainly we are looking at that and we expect that we’ll be having discussions on clinical trials as they come forward. So thanks very much for that question.
Robert Miller: Thank you.
Donna Pearson: Thank you very much. There is substantial confusion between the disease that you’re studying and other conditions involving unspecified chronic fatigue and that confusion impacts research, medical education, diagnosis, treatment and care at every level. And I know that the name is not an issue that many people want to talk about in research. However, a name is the single most obvious way to distinguish a disease from another disease, and the IOM clearly agreed that a name-change is appropriate and suggested establishment of a new ICD code.
So my question is, does the current study and the tests that you will be doing have the potential to determine if encephalomyelitis is in fact an appropriate name for the disease?
Dr Koroshetz: I’m not sure if Avi is still on the line?
Dr Nath: I’m here, I’m here yes. So, you know, we’re not looking at every single aspect of the disease: we’re looking at a select population, and in that population we can finally tell you if there’s evidence of inflammation. And if there’s evidence of inflammation then I think it’s fair to say that the [inaudible] inflammatory process is the brain. Whether you would call it [inaudible] encephalitis… the problem is that you have to demonstrate that there’s infiltration of cells, yes? Activation of the immune system in the brain alone is not sufficient to cause encephalitis.
You can get activation of the immune system in patients with Alzheimer’s disease, with Parkinson’s disease… we don’t particularly call that encephalitis. But I think we will get closer to that answer, because we will be able to look at a panel of cytokines and we may have some suggestion as to what kind of cells are producing those cytokines. And so, yes, we’ll get closer to that definition.
Whether we are able to establish it beyond an element of doubt or not won’t be from this study. We are planning some animal studies and I think that will be a better chance for being able to answer this. So the animal studies will take lymphocytes from the patients, inject it into the animals, and try to reproduce the disease. If we can, then we can look at the brains of the animals and actually tell [inaudible] or not whether we’ve produced the phenotype or not. I think both kinds of study have a much better chance of being able to answer the question that you addressed.
Dr Koroshetz: Let me just add a couple of points because I think they’re important to understand. I’d say that the protocol at NIH is interested in trying to get at the biology – the biological basis of the illness. Now, eventually that might… the biologic basis of the illness in most other illnesses is eventually what moves the definitions and allows break-up in the heterogeneity of a disorder into particular biological entities. That process is a long process, and so I would urge people to basically stay the course there.
Clearly this protocol, which is looking currently at 40 patients… what they find will then need to go into another stage to be validated in other groups of patients to make sure that it’s a real finding that can be generalized. So generalizability is the next step that would come when a discovery is made.
One reason we think it’s real important to organize ME/CFS researchers across the country is because many studies have discoveries but they’re never really validated to know if they’re generalizable, and so I think we have a lot of clues in the literature but one thing we need to do is to make sure that they can be generalized across the population.
And the expectation is, I think, that there are multiple different types of ME/CFS and something we find here may not generalize. This protocol is for persons who develop the condition after a flu-like illness. There are other ME/CFS patients who develop the condition after other types of exposures: environmental exposures, allergic exposures, traumatic exposures. So we can’t solve the whole problem with this one protocol. This is again, a piece of the puzzle. I urge people to think of it in that way.
OK, if we go to the next question?
Cort Johnson: Thanks. As I’m sure you’re aware, Ron Davis is undergoing… he’s taken on a similar exploratory study and so what I was wondering was if it’s possible for Davis to follow up on findings that you get and vice versa, can your team follow up on findings that he gets? Is it possible to give him some funding to be able to do that?
And my second question involves the exercise study. Staci Stevens and Workwell have worked for years to develop standardized exercise protocols that work for ME/CFS patients. The exercise portion of the study is probably a critical part of the study. Is the team planning to contact her and work with her to be able to use a similar protocol in their study?
Dr Koroshetz: Brian, could you address the exercise protocol, and Avi, maybe you could address the data-sharing next.
Dr Walitt: So the exercise protocol for the study that we’re doing at the intramural programme is designed to induce post-exertional malaise. It’s a maximal-effort exercise intervention. It’s designed to provoke symptoms, as opposed to being a treatment. The CDC, Beth Unger, has a lot of experience in doing this kind of work and we’re going to be talking to them about designing proper ramps and so forth.
However, we are open to suggestions from all people with experience and I would be happy to reach out to others that may have useful things to add as we design the intervention.
Dr Nath: This is Avi. Let me just add to that. So I did talk to Dr Davis and we’re absolutely delighted to collaborate with him. The kind of study he’s doing is not exactly the same as we’re proposing to do. So I discussed that in great detail – we actually exchanged a number of… [Dr Nath’s line cuts out.]
Dr Koroshetz: I think we dropped off Avi. But I think his point is that, yes, he has been in contact with Dr Davis and actually a number of other investigators around the country who are collecting samples and they will be sharing data. Now, I think also, as we mentioned, what we’re hoping to do is to set up a series of investigators around the country who can work in concert with each other and share data, particularly with regard to looking at the second issue I mentioned before, which is generalizability – can you… if you find something in one group and you check another group that you think is similar, do you see those same findings or not?
Unfortunately, the history of these kind of biomarker studies is such that it’s… a lot of things fall out and don’t replicated, so you really need to do this coordinated approach to make sure that what you’re putting your money on is a real thing, a real finding.
OK, can we go to the next question?
Charmian Proskauer: Hi – thank you very much for this opportunity to have a discussion. I think this is great. You may have already answered this question in parts through things that you’ve already said but I’m going to ask it anyway. Why only 40 ME/CFS patients? I realize that this is a very deep study, but with 40 patients, does that have the danger of falling into the category of just another pilot study with numbers too small to be really meaningful? That’s my question.
Dr. Nath: So let me address that. This is Avi. There are two aspects to it. Number one is that we are going to be screening patients, that’ll take us a while. The we admit the patients and they’re going to be in for a week. So it will take us one patient for a week. Give and take 40 patients, it’s going to take you a minimum of one year just to study 40 patients plus you’ve got the controls so it’s going to take you a while to actually get through this population. So If you increase it more and more it’s going to take you longer to get to the answer.
The other thing is that we’re collecting a very precise population. [inaudible] we’ve calculated a lot of sample sizes based on the information that we have. If you don’t find a neuroimmune abnormality in 40 then it’s unlikely to be a major driver of the disease. And I’m pretty certain that this is a decent sample size for us to be able to find the kind of immune abnormalities that we’re looking for.
So I think the sample size is pretty decent and it gives us an opportunity after that, as I said, to do a longitudinal study and then you can enrol as many patients as you want from, you know, all over the country and other people can participate in the study and take those findings and look at multiple groups. So you have the second phase of the study that allows you to do a more expansive study but you don’t want to do a huge expansive study the first time around. If it takes a thousand patients to find something, it probably isn’t worth chasing at all.
Dr Koroshetz: I think I’d also add that at NIH, there’s a culture which is actually to try to learn as much as you can from every single patient, so there are for instance an undiagnosed disease clinic here where people come with diseases that could not be diagnosed on the outside and they’ve found causes for many of these patients. They’re all different, though, so I think… you know, it’s also possible that, with the kind of in-depth analysis, that there may be very robust findings in even one or a small group of patients that will be very important.
So it’s a little bit different. It’s definitely not an epidemiological study. This is… the NIH is much more… its advantage is in deep study of small numbers. But I think as the question posed, the issue that… to actually get the answer for all the patients who have ME/CFS, this is just one step and we have to see what we discover and how generalisable it is to the population, and that’s going to require multiple steps and a larger group of investigators. Can we go to the next question?
Joni Comstock: Hi. I represent MEAdvocacy, a grassroots non-profit organisation advocating for patients suffering from ME. Our emphasis is the severely affected patients, most of whom are homebound and bedbound. Some are so sick they’re unable to care for themselves. We were dismayed to learn that the protocol and design for the intramural study has been well underway without any input from the ME/CFS expert clinicians, researchers, as well as from the patient and advocate community. This became even more disturbing as so many flaws were revealed about the study. These deficits showed us that many of the [inaudible] misconceptions of the disease still exist and have not been clarified.
Therefore, we initiated and delivered a petition of 725 signatures to Dr Collins to stop the study and start it from scratch with stakeholders’ input from the get-go. Because of ingrained institutional misconceptions, whether deliberate or not, we expect the NIH to engage the expert community on any ME/CFS study from the moment of its inception. They should have input throughout the entire process. This includes the planning and implementation of the design, recruitment, trial, analysis, study outcome, peer-reviewed publication, and the publicity. Do you intend to respond directly to ME Advocacy about the petition, and how do you plan to incorporate our concerns?
Dr Koroshetz: Well let me just to start…..I appreciate your concern and our intent is to reach out and get input from a wide variety of folks with expertise and with experience in this illness and we have been doing that right from the beginning. At NIH, through the Trans-NIH Working Group, through the CFS Advisory Committee, we’ve had multiple meetings with experts in the field and with advocacy groups.
I must say it has been a challenge for us because there are… we may not have reached out to everybody, and we apologise for that. It’s very difficult to know exactly who everybody is, and that’s the reason we have these calls, and this is not going to be the last of our calls, but it’s only the beginning.
And we will learn from patients. I think the history of medicine is that, as you work with patients, the patients teach you lessons. And so I think that the major teachers at the NIH really have to be the patients who have made the sacrifice to join the protocol, to come in to the Clinical Center, and to work with the doctors. I think that’s where a lot of the input’s going to come, and the protocol itself – Brian can correct me if I’m wrong – but the protocol is always a work in progress, so the protocol gets put up, it has to get approved, then it moves forward, then there are amendments, they have to get approved again and then it moves forward, so…
And the protocol is something that’s going to have to be tested. It’ll probably mean bringing in control persons to see if they can manage the protocol as it stands before we bring in patients with ME/CFS and put them through the protocol as it stands. So I think we are definitely interested in getting input.
But in truth of the matter, the scientists at the NIH have to be the ones who are powered to work with their patients to try and get at the bottom of these……what is the biologic nature of ME/CFS. So we are very anxious to move ahead and we can’t take all patients with ME/CFS. So the very severe cases who are homebound I think we’d certainly not be wise to start there. I don’t know, Brian, do you have any points on that?
Dr Walitt: Part of the protocol is to look at post-exertional malaise, which requires pushing patients a bit and being able to exercise, and being able to do things. Taking a homebound population and stressing them more may lead to untoward consequences for the patients and we need to be concerned about those things. It’s definitely a very important population to study but that might be for the next phase.
Dr Koroshetz: Right, and I also think the Clinical Center does have the ability to bring people into the hospital who are in very poor condition, because it is a hospital, it has 24-hour nursing, so it is something that we could potentially get to at some point but I think it would be probably unwise to start there.
So again, I apologise to the community for the perception that we’re not listening, because we are very much listening and we will continue to listen and we will continue to communicate the best we can. So thank you very much for that. Can I have the next question, please?
Lily Chu: Hi, good morning. This is Lily Chu, I was one of the co-authors of the IOM report. I’m also the Co-Vice President for the International Association for CFS/ME, but my comments today are my own individual views. So I have two points. One is about the study itself and the second is about the staff.
One of the things I found when I was reviewing the literature for post-exertional malaise, is a lot of literature only looked primarily at fatigue as a symptom, and I’m trying to review the website you have up right now, and again, it says that you’re going to have a diary of people recording their symptoms for at least a week once they’re back home, and that’s good, but it says “fatigue symptoms”. So what I would suggest is, PEM is more than fatigue.
In the report, we talked about things like people having problems thinking, problems having problems sleeping, sore throats, enlarged lymph nodes, all of the muscle pain. So what I would suggest is that you ask for more symptoms than just fatigue, and that you leave some open-ended areas where people can put in their symptoms.
The second thing is timing, so most studies, they just pick a period like two days, and that’s when they collect the blood tests or their other tests, and their symptoms, of patients. And what I was finding from reading the literature and talking to patients and some data I have and am analysing right now is that the timing of PEM can vary a lot. So ideally, it would be nice if you could time the tests to where people are saying, “this is the peak of my PEM”. Or even have it after one day or two days because sometimes people’s PEM does not start until several days after whatever the triggering event, and in this case, it looks like you’re using a treadmill to induce the PEM. So that’s my point about process.
The points about staffing – I’m really glad you have some experienced people on this project, including Dr Lipkin, but one of my concerns is that you have both Dr Walitt and Dr Gill on the staff. And I’m sure you’ve heard a lot to some degree already about Dr Walitt.
My concern about Dr Gill is, back in 2011, he did a talk for NIH and he had a lot of slides in there about pacing – not about pacing, but about graded exercise therapy, cognitive behavioural therapy, and about not ordering certain tests, like for example tilt table testing because they weren’t suggested by the CDC at the time. And so there are some concerns there – I can send you links – where a lot of the community had concerns about Dr Gill, and I even wrote Dr Gill a letter before his talk. I hope that his views have evolved and changed since then, so if he’s changed, that’s great, but I have a little concern about that.
Even if you have the right people for selecting the patients, if the people interpreting the study have certain biases – and we all have biases – but it does need to be recognised when they go in to analyse or interpret the study. So I’m wondering if the staff that’s on the study, are they going to be reading things, like the IOM report, the NIH Statement of Knowledge conference report from 2011, even, and the AHRQ and NIH reports more recently.
Dr Koroshetz: Thanks very much for that, I’m going to ask Brian to talk a little bit about the protocol with regard to the symptoms you mentioned, the time to peak and then the [inaudible] working on the protocol.
Dr Walitt: That’s a very good point, that… what exactly post-exertional malaise is has been poorly explored to date. What we’re going to try to do here at the NIH is to induce it and describe it as it happens. This will be done qualitatively by speaking with the patients and listening to what they have to say and hearing their descriptions of it.
We may even do a qualitative study of the words that are used to describe it, as well as biologic measurements that are taken sequentially, starting before the exercise and following it over the course of their hospitalisation, in the hope that doing all sorts of different biological measurements that try to capture different aspects of the biology of post-exertional malaise. And so your comments about timing are very true and we are taking that into consideration.
Dr Nath: I want to address another issue. (This is Avi.) Throughout the protocol, there will be continuous seminars, series, journal clubs, so on and so forth, so that the team that is working on the protocol becomes well aware of the existing literature, the emerging literature, the pros and cons and the [inaudible] of the previous protocols and the previous studies as well.
We’re going to have invited speakers come and talk to us so that we have a cutting edge knowledge and state of art knowledge and state of art techniques that we’re using in order to study the syndrome. And that probably connects all our other protocols, that’s no different than we would do for my other protocols as I would do for this.
The other thing is, the way I’ve designed the study, there’s no element of subjective bias, because really what I’m looking for immune abnormalities. So it’s going to be done in my laboratory, it’s going to be done in the Center for Human Immunology.
And although there’s 26 investigators there, there are about… if we include the people in various laboratories doing the study there are about 150 people. So there’s a huge number of people collating the study, I ultimately interpret all of these things and then we will make the findings available to everybody, and there’s an advisory group that looks over our study as well as our findings. So I’m not really concerned… [Dr Nath’s line cuts out.]
Dr Koroshetz: So Avi dropped off again but I think the point is that NIH is a very unusual place and that the people are here to try and get at the bottom of problems and they have really the strictest scientific minds and I’ve rarely, if ever, seen what you might call a personal bias affect a study. So I think everybody here is really devoted to just getting to the bottom of the problem. I really do not see any chance that this is going to be corrupted at all. This is a very unusual place where there’s very little incentive… and actually, it’s a career breaker if that ever happens. So I really do not feel that this is a concern that the community should worry about. So thanks very much….
Dr Nath: The design of the protocol is not going to allow any of that anyway.
Dr Koroshetz: Yep. OK, great. Can we go to the next question?
Jennifer Spotila: Thank you, and thank you to everyone on the panel, especially Dr Collins. I appreciate your personal appearance here today. I have, as you can imagine, a million questions – I’m going to focus on three.
First question for Dr Koroshetz: can you make a commitment to this community today that a request for applications with set-aside funds is going to be part of the short and long term strategy coming out of the Trans NIH Working Group?
My second question for Dr Nath or Dr Walitt is why the selection of Lyme disease as a comparison group? There’s a lot of overlap in the chronic Lyme community and the ME/CFS community – people being diagnosed with one when they may have the other – and also there’s a question about the reliability of the testing. So if you were looking for a post-infectious group with no sequelae, I wonder why something like resolved influenza might not be a better comparison group.
And then the third question for Dr Whittemore is how are you going to systematically incorporate patient and subject-matter expert input into this study and into the formulation of strategy? I think these town hall meeting calls are a great tool for you to use but it shouldn’t be the only one and I know I would really like to see some more systematic involvement of both patients and subject-matter experts throughout the phase of the strategy. Thank you.
Dr Koroshetz: Thanks very much. Let me talk a little bit about the first question which was the commitment of funds and RFAs. So given the processes I mentioned at NIH, I can’t really say that. I can tell you that that’s our goal. That’s what we’re working towards and we’re hopeful but I couldn’t say publicly what we’re going to be able to do until we have a plan that we can make public. So I hope that’s helpful.
In terms of the Lyme disease, Brian, would you like to take that one?
Dr Walitt: Sure…
Dr Nath: I can handle that. This is Avi.
Dr Koroshetz: Avi? OK.
Dr Nath: The reason I asked for the Lyme disease group is because… there are two reasons for it.
Number one is it’s a patient population of convenience for us because Adriana Marques, who is an infectious disease expert at NIH, has a patient population… She specialises in Lyme disease so she already has a well characterized population of patients who we know for certain had Lyme disease and they did get better or they did not get better. And so we could very easily recruit some of the existing cohort.
And so when we thought about, OK, what we want to control for… this is not chronic Lyme disease, so that’s the other thing I want to make absolutely certain. These are individuals who had an infection and they did not develop any other chronic symptoms. They’re fully recovered. In that sense they’re pretty close to the healthy normals because normal individuals also develop infection at some point in time and most healthy individuals recover from it. But here this is a specific infection, a sample size of individuals already exist at NIH and we can easily recruit from them.
They’ve already been studied at great length so we can actually use the information that already exists on them. So all those things considering… that’s why we chose them this time. Not that the influenza population is not worthy of studying – I think they would be fine, too – but we picked this for the reasons that I mentioned.
Dr Walitt: If I can also add that onset of Lyme disease has some very specific physical findings, in particular the rash of Lyme disease that helps us understand exactly when the infection started. And so when we’re trying to look at people that are after the infection, it makes it easier to figure out actually when the infection started, and pin down the time.
Dr Koroshetz: Vicky, do you want to talk a little bit about the engagement of the community as we move towards extra-mural plans.
Dr Whittemore: Sure. So for the involvement of the community with the Trans NIH Working Group we’re thinking about initiating a period of time with each of our Working Group meetings when we can open the lines and have input and/or potentially presentations from various members of the community, again using our website to push information out and also to get feedback from the community would be really helpful.
And I think we’re also always open to any thoughts that the community has. We’re thinking about some workshop ideas where we would involve the patient and clinical and research community in the organization and putting that together and also then welcoming patients to attend that meeting.
I’ll let someone else address – maybe Avi – address involving patients in the study… intramural study.
Dr Nath: Can you say that question again about involving patients as advisors or…
Dr Koroshetz: I think she’s asking about the patient advisory group, Avi.
Dr Nath: Oh, OK. So we looked into some of the legalities about patient advisory groups and it’s a little bit complicated at the federal government but nonetheless what we are absolutely committed to is getting input from patients throughout the study itself.
I think some input we’ve already received and we’re going to come up with a system whereby we can get continual input from patients and patient advocacy groups as the study goes forward.
As Dr Koroshetz mentioned earlier, the protocol is a process of evolution. Just because you wrote up the protocol doesn’t mean that’s exactly the way it’ll be conducted. A lot of changes that occur to the process. And so continual input is necessary throughout the life of the protocol. And so we’re happy to receive that and we’re happy to work with the patients and the advocacy groups for that purpose.
Dr Koroshetz: I think that also the patients who enroll are going to be… they’re going to have a lot of influence on the [inaudible] and how it moves forward.
Wilhemina Jenkins: Good morning. I’d like to especially thank Dr Walitt for being here and I understand that Dr Nath spoke specifically to the importance of keeping personal bias out of any research that goes on but I wonder if Dr Walitt, just to allay the fears and concerns of the community, could speak directly to that himself and I’m sure you understand the fears of the community based on many studies that have taken place, particularly the PACE studies in England that we are very concerned about, that problem of bias within a study, that it has been shown to affect the results.
I understand Dr Walitt has worked with patients and I would just like to hear him speak again about how his own view of this illness will be incorporated within the study or will not affect the study.
Dr Koroshetz: Thanks very much. Brian?
Dr Walitt: First let me affirm by saying that chronic fatigue syndrome / myalgic encephalomyelitis are a biological disorder. Research has shown that in every system of the body that has been investigated that there have been abnormalities when compared to healthy volunteers. If chronic fatigue syndrome / myalgic encephalomyelitis is all in your head, it’s only because your head is part of your body.
In regard to my individual role in the study, I am serving merely as a facilitator of research, helping to coordinate all the scientists and all the medical professionals that are required to make this happen and to help provide care and to be a cheerleader for the patients as they come through the door.
I don’t have a bias. I don’t have an outcome that I hope to see except that we find an answer that makes people better.
Dr Koroshetz: Thank you very much, Brian.
Unknown speaker: We have time for one last question. Let me just fill the gap by saying I know there are others of you waiting to ask questions of us.
Thank you for your participation this morning and send us those questions. Please send your questions to email@example.com and we will make our best effort to respond to you in a timely manner. Thank you again for participation. One last question.
Rivka Solomon: Thank you very much for holding this meeting today.
So I’ve been sick 26 years, much of that homebound and bedridden and it’s obviously devastated my life and at least a million other patients are suffering with this illness in this country. I think that we need equitable research funding at a level that’s commensurate with the degree of disability and with the population numbers.
I know this is the first step, you’re saying, but in my mind and in many patients’ minds we need probably something along the lines of $250 million a year to be able to address this illness properly and that doesn’t even count the thirty or so years we’ve missed. Could somebody address that please?
Dr Koroshetz: Thanks, Rivka. Yes, I think for this, as unfortunately as well for many diseases, the amount of research funding does not match the burden of illness. So all the diseases… So in our institute we have probably 300 different neurologic diseases and that’s the case for every single one of them.
That being said, the process by which NIH deals with how to allocate these scarce resources is this tried and true process that’s been in place for 50 years where investigators submit grants, and they get peer reviewed and they get scored, and then the NIH starts to pay the ones that are seen to be the most highly meritorious and go down the list until we run out of money.
So the system is a peer-review system and what we need in some diseases, and I think in ME/CFS, we need funds to fertilize the research, to get the research going, to get really a large number of highly motivated and well trained investigators into the field, and that’s what we are planning to do in a fairly short time is to try to get that growth of investigators but the truth of the matter is to really get the funds towards ME/CFS to a high level on par with many other like diseases, we need those kind of applications to come in and compete against and in a fair way with the other disorders.
And so I think this is a short-term process that we definitely have to stimulate with funds that are particularly for ME/CFS, and Dr Collins is clearly behind that.
But our hope is that this will actually spread, that the community will come in and begin working with investigators at universities and clinics throughout the country and that groups will form that will submit applications that are clearly incredibly important and high-level science that gets to the bottom of the problem.
So I think again we have to utilize the NIH resources as best we can for the long term and I think we can do that but we cannot do it alone and we need to do it with the patients and the advocacy groups together, working hand in hand as we try and fight this illness.
So I want to thank everyone for coming on. We’re out of time. We will certainly be looking at the questions that get submitted and we will again set up another call where we can continue the dialogue that we started today and I can’t say how much everyone around the table and Dr Collins appreciates the interest and the concerns of the community. It’s really been fantastic. So thanks very much.
Unknown speaker: Please send any of your unanswered questions to firstname.lastname@example.org. And for those of you who aren’t near a pencil and paper, you can go to the main NIH ME/CFS website and simply click on “Contact us” to submit those questions.
Thank you again for a very productive discussion this morning.
NIH has said it will be releasing a recording of the call to the public by early next week.
Stay tuned to #MEAction for current updates as new information is released.