Occupy CFS

The good news, I guess, is that we survived another CFS Advisory Committee meeting. The bad news is that much of what happened made no sense to me. Some excellent summaries of the meeting are available, including this very detailed recap from Phoenix Rising. I would like to tackle a few of the topics that had me shaking my head, or asking myself if my experience of reality is so at odds with the Committee’s. This post is long, and I apologize for that. Here’s my report card on these head-scratcher issues:

• Meeting Mechanics: C
• High Priority Recommendations: C
• Invisible Information: D
• CDC: D
• Case Definition: D

Meeting Mechanics

I know how difficult it is to prepare for and moderate two full days of contentious meetings, and I imagine it is more difficult to do so when the meeting will be held in public. However, I was struck by how poorly some of the administrative aspects of this meeting were conducted. For example, the procedure for meeting and comment registration is unnecessarily complicated for a patient population that struggles with multiple forms of cognitive dysfunction. I hope this can be simplified.

On the first day of the meeting, Dr. Gailen Marshall said that members would be limited to three minutes for comments during discussion. He did not enforce this limit evenly, including on himself. More than one observer noted how long his own comments were, and how he sometimes monopolized discussion. I happen to think that a Chairman needs leeway to cover certain topics, but sometimes this seemed excessive. Participation by other Committee members is very uneven: Eileen Holderman, Dr. Mary Ann Fletcher and Steve Krafchick speak most frequently; Dr. Jordan Dimitrikoff and Dr. Susan Levine fall somewhere in the middle; Dr. Adrian Casillas, Dr. Lisa Corbin, Dr. Dane Cook, and Rebecca Collier rarely if ever spoke. It did seem like the non-voting liaisons were integrated into the discussion, and had opportunities to ask questions and offer feedback.

I was very frustrated by the evident lack of preparation for even simple agenda items. For example, when approving the list of ME/CFS organizations for linking on the Office of Women’s Health website, the Committee did not have a list in front of them and they approved the criteria on Day 2, after approving the list on Day 1. One of the criteria was that organizations would consent to being linked, but on Day 1 Dr. Lee said that was not checked, so the criteria list on Day 2 had to be amended. It was a mess, and hard to follow. A similar lack of preparation was evident in the discussion of the High Priority List, as we’ll see. There is simply no good reason for the lack of preparation. Why didn’t a staff member type up the list of criteria and list of organizations, provide it to the Committee and post as a slide, so everyone knew what they were voting on? The disorganization and confusion wastes time, at the expense of other issues.

One mechanic that worked fairly well, in my opinion, was the audience Question & Answer. The audience questions led to some very significant discussion, especially regarding CDC. Some people feel that Dr. Marshall should not curate these questions, and I thought that the “answer” discussion tended towards domination by the Committee instead of actual answers to the questions. However, I think the value of this kind of interaction was very clear and I hope this will continue.

High Priority Recommendations

From a procedural perspective, we scored a small victory here. Dr. Marshall acknowledged that the list was not handled correctly last year. I pressed the Committee to devote an appropriate amount of time to discussion of the list, and I was shocked when they agreed. I don’t know what happened at lunch, or who said what, but apparently there was enough concern expressed that Dr. Marshall said they would move the discussion to Day 2. They discussed the list and how to use it going forward, and voted on it in public as required by FACA. Procedurally, they handled the issue correctly.

But the substance of their decision is perplexing, at best. No list was posted, and it did not seem like the committee members had a single piece of paper in front of them with the full list. Items were added – but without reading some of the additions into the record – and a process for removing items was discussed but not used. Dr. Marshall downplayed the fact that several recommendations had been altered from the original form, saying that “the spirit is there.” Dr. Lee said that the old recommendations chart would now be a historical document, and the High Priority list would be the working list. Dr. Marshall said that of the eight recommendations the Committee made last year, three were complete and the other five would be added to the list. But he did not specify which recommendations he considered complete, and no one asked him to be specific. I can make a pretty good guess, but we won’t know for certain until the final list is posted.

And amid all this back and forth, Dr. Marshall said that the list was never intended to prioritize one recommendation over another within the list. Everything on the list is of equal importance. No one questioned or objected to this. This may not seem like a big deal, but it is. By acquiescing to this equal priority description, the Committee created a situation where holding a disability workshop is of the same priority and importance as holding a case definition workshop. I don’t think most members would agree with that statement, but now they’re stuck with it.

So what did they select as the high priority recommendations? The Committee combined the original seven recommendations on the January 2012 list, five of the eight recommendations made in 2012, and two recommendations added by Eileen Holderman. These items are listed in chronological order. New recommendations will be added to the list automatically, and the Committee will have to vote to remove an item once they are satisfied with the response from the Assistant Secretary. I’ve drafted my best guess at the specific recommendations they approved (given the lack of precision on the 2012 recommendations), and I’ll post the official version when it becomes available. Is this list ever going to matter? Technically, I think it matters a great deal but I’m not sure the Committee shares that view.

Invisible Information

One of the things I said we should watch for at the meeting was any mention of the Ad Hoc Workgroup. Guess what? They never mentioned it once. This is one of the things that has me questioning if my reality is different from the Committee’s. Dr. Lee made such a point of talking about the Workgroup in 2012, and their report was published in March. But at this meeting? Total silence. It’s as if the Workgroup doesn’t exist. And not a single Committee member brought it up or asked a question. Why? What is the status of this group? What did the Committee think about the report? Did they even READ the report? Am I the only person who thinks this is strange?

The other thing that received almost no attention is the response from the Assistant Secretary to the Committee’s October 2012 recommendations. This was posted to the CSFAC website shortly before the meeting (pdf link). Again, I don’t understand why the Committee doesn’t simply review these at the outset. Instead, the only discussion was when Steve Krafchick objected that the response to the recommendation to hold a case definition workshop was not actually responsive (see the discussion on case definition below for more details).

The risk of ignoring or glossing over the official responses to CFSAC recommendations is that we miss opportunities to understand the basis for those responses. For example, buried on page 3 of the response is this statement: “To date, CDC has not been able to confirm the occurrence of outbreaks of CFS.” This leaves me wondering how in the world CDC characterizes the outbreaks at Incline Village and Lyndonville. But because the Committee does not discuss the responses, these questions don’t get raised. If I write to CDC or submit a question for the next PCOCA call, I will probably be ignored. But a CFSAC member could ask these questions and get answers on the record. Instead, this information – and the opportunity to learn even more – is effectively invisible, and it has no apparent effect on Committee members and discussion.

Oh CDC, You So Crazy

The CDC’s report of activities was ho-hum, dry, and devoid of much of interest. It was not until the Q&A sessions that we actually learned anything important.

The very first question was whether CDC would use the two-day cardiopulmonary exercise testing in phase 2 of its multisite study. Dr. Unger said that the clinicians in the multi-site study felt a two-day exercise test was “not advisable.” She elaborated that patients travel some distance to get to the physicians involved in the study and that a two-day test was not feasible. It was not clear to me whether the concern was the time required or the physical impact on the patients. I was very surprised that the clinicians (Natelson, Klimas, Peterson, Kogelnik, Bateman, Lapp, Podell) were the ones who advised against using the test because most (if not all of them) have used two day testing for some of their patients. Steve Krafchick pressed Dr. Unger, stating the importance of two day protocols for exercise and neuropsych testing in order to objectively capture the effects of post-exertional malaise. Dr. Unger said they would rely on questionnaires for functional outcomes and the clinicians’ observations of clinical course. Krafchick said it was a mistake to eliminate the testing, and asked if Dr. Unger had talked to Dr. Chris Snell. Dr. Unger said, “No.” My jaw hit the floor. How could it be that Unger has never talked to Snell about CPET? They’ve been at meetings together, including the recent FDA meeting where Snell gave a presentation on two-day CPET. I still can’t wrap my brain around this. Two day CPET provides objective evidence of metabolic dysfunction, post-exertional malaise and estimate of disability. CDC, how could you refuse to use this test?!

Another great question for CDC was whether the website would include a highlighted warning that exercise can be dangerous for ME/CFS patients. Dr. Belay answered that the website states exercise can exacerbate the illness, and Dr. Marshall asked about the equivalent of a black box warning. Dr. Belay said they could consider it. Dr. Fletcher followed up with a reminder that the Toolkit recommends exercise as a therapy, and Dr. Belay said CDC has revised the Toolkit and it is going through clearance. My jaw hit the floor again. Why didn’t Dr. Belay think to mention that in his routine report? It’s obviously of interest to the Committee since they recommended last year that the Toolkit be removed from the website. I guess Belay was planning to wait until the revision was complete, because when Steve Krafchick asked if Committee members could see it for review or comments Dr. Belay responded, “Why?” and “we don’t do that.” Seriously? Dr. Marshall pointed out comments could be useful, and Dr. Lee said they could send informational copies to interested members for feedback.

The Committee discussed a review of the CDC website, including the photos which portray people yawning at work, going for slow walks, etc. Several committee members (and many patients) feel the photos are misleading because they do not portray the seriousness of the illness. Dr. Unger responded that they want to portray a “positive” side. Seriously? To be frank, it is conversations like this one that make patients wonder what planet CDC lives on that they think there is a positive or lighthearted side to ME/CFS. The discussion moved into case definition because the CDC website and medical education material lists multiple criteria, including the maligned Oxford definition, even though CDC says it endorses and uses Fukuda. There was more discussion of the 2-day CPET, whether the Canadian Consensus Criteria is difficult to use, and whether there was enough information to endorse the Canadian Criteria immediately as many advocates insist. Unfortunately, and typically, there was no resolution on any of these issues and case definition raised its ugly head again and again.

A Rose By Any Other Name . . . .

So we come to case definition. In October 2012, the CFSAC recommended that the Secretary:

promptly convene (by 12/31/12 or as soon as possible thereafter) at least one stakeholders’ (Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)experts, patients, advocates) workshop  in consultation with CFSAC members to reach a consensus for a case definition useful for research, diagnosis and treatment of ME/CFS beginning with the 2003 Canadian Consensus  Definition for discussion purposes.

And the Assistant Secretary responded in writing on May 1, 2013:

The National Institutes of Health (NIH) is convening an Evidence-based Methodology Workshop process  . . . to address the issue of case definitions appropriate for ME/CFS research. However, it will not cover in detail a clinical case definition. The Office of the Assistant Secretary for Health, Department of Health and Human Services, is actively pursuing options for a separate effort that would work in coordination with the NIH process, but result in a case definition useful for clinicians who see patients with symptoms that may be ME/CFS. . . . .

The EbMW consists of a thorough, unbiased evidence review of the literature related to clinical research outcomes compared across case definitions and culminating in a workshop composed of experts and patients. The workshop participants and panel members will use the evidence review to evaluate the strength of evidence for case definitions with the goal of identifying the most consistent outcomes. . . . The first organizational meeting for the EbMW on ME/CFS was held on February 19,2013. A timeline for the process is being developed.

The wording of the response is very important: the EbMW will address the issue of case definitions appropriate for ME/CFS research. That does not say they will identify the correct or new research definition – just that the issue of appropriate research definitions will be addressed.

These two paragraphs from Assistant Secretary Koh’s response translate as follows: 1) No, we will not have a stakeholders’ workshop as you recommended in October 2012. 2) We will have an EbMW to address definition issues related to research. 3) We are “actively pursuing options for a separate effort” on a clinical case definition.

Understandably, several CFSAC members were upset that the answer was No-but-we’ll-do-something-else. This is what led to the fireworks at the end of Day 2. Several members reacted strongly to Dr. Susan Maier’s report that the unidentified people who attended the meeting on February 9th submitted a list of 35 to 40 potential candidates for the EbMW’s organizational committee to the Office of Disease Prevention for vetting and selection. Dr. Maier could not identify that list of candidates, although she did say that there were CFSAC members and advocates on the list. We have no timeline for publication of this list, either. Dr. Fletcher was particularly vocal about the secrecy and long timeline

I have to say that I am not surprised that the answer was “no, but . . . ” and I’m not knocking the EbMW. Dr. Beth Collins-Sharp from the Agency for Healthcare Research and Quality gave a detailed explanation of the methodology used for evidence reviews, and it is quite robust (and includes a patient viewpoint). I suspect that this is the same kind of evidence review that was requested by the CFSAC years ago in order to have a State of the Science Workshop, and which was never completed. The State of the Knowledge meeting in April 2011 was basically a State of the Science-Light kind of meeting. AHRQ’s last review on CFS was completed in 2002, so it is certainly time for an update.

The problem here is that we don’t have enough information to judge the EbMW process, since we don’t know who is on the organizing committee. We can’t judge the case definition process, since we have absolutely NO information about it whatsoever. And this leads to the real problem: THIS IS TOO SLOW.

As Dr. Wanda Jones reminded us in her welcoming remarks on Day 1, government moves slowly. It does indeed, and this creates extraordinary frustration for every patient and advocate involved. It seems unlikely (at this point, anyway) that the Canadian Consensus Criteria will be adopted as an interim measure, and none of the other case definition processes will bear fruit within the next six months. The government apparently expects us to wait patiently and calmly as this process unfolds at a bureaucratic pace. We don’t have a choice about the waiting part, but I don’t think the expectation that we will be patient and calm is realistic at all. This issue is too huge, too important, too divisive, and too slow. People are angry and will continue to be so, unless the government can demonstrate urgency.

If anyone from HHS is reading this post, may I suggest that you improve the way you communicate around this issue as a first step? The FDA communicated openly with us, and also produced a great meeting. Look to FDA for ways to productively and positively engage the patient advocate community. If you don’t, we are likely to see fireworks of one kind or another at every CFSAC meeting going forward.

 

The CFS Advisory Committee will meet on Wednesday and Thursday this week (May 22nd and 23rd). The meeting will be webcast, and I’ll update with that information as soon as it becomes available. UPDATED: To call in to the CFSAC in listen only mode: 1-866-500-6250, participant code: 9487727.

UPDATED: WATCH THE MEETING LIVE

The full agenda has been posted, and I’ve put together some things you can expect and watch for at the meeting.

New Faces – You may recall that Dr. Jacqueline Rose resigned after the June 2012 meeting. Her replacement has been appointed: Rebecca Collier, RN. All we know about Ms. Collier is that she is a registered nurse, and that she nominated herself to the Committee in 2011. I’m looking forward to learning more about her at this meeting. This will also be the first meeting attended by the nonvoting liaison representatives from the CFIDS Association, IACFS/ME, and the New Jersey CFS Association. We don’t really know how the liaisons will be integrated into discussions, or how their expertise and perspectives will be considered.

Missing Faces – Dr. Ann Vincent recently resigned from the Committee for unknown reasons. Other missing faces will be those of many patients who regularly attend the CFSAC meetings. Most of the advocates I know are still recovering from the FDA meeting and are too ill to make the trip, myself included. The room may look a little empty.

Official Presence – For the past several years, Assistant Secretary for Health Dr. Howard Koh has briefly attended the CFSAC meetings to give an official welcome and review highlights of the Department’s work on ME/CFS. He is not listed on the agenda for this meeting. Instead, Principal Deputy Assistant Secretary for Health Dr. Wanda Jones will give the official welcome. Dr. Jones is well liked by patient advocates, so this is not necessarily a bad thing, but it will be concerning if Koh is stepping back from his involvement in the CFSAC.

Agency Actions & Accomplishments – In March, the HHS Ad Hoc Workgroup published its first report. There really wasn’t any news in that report, but I expect the Department will cite this as a significant accomplishment. I hope we will hear about the future plans for the Workgroup, and whether they will actually stimulate new programs for ME/CFS.

High Priority List – Dr. Nancy Lee assured Public Citizen that the High Priority List would be fully discussed at this meeting. However, the current agenda allocates only 30 minutes for the approval of both the Priority list and the proposed list of organization websites. I honestly don’t know how there can be “full discussion” of the list in less than 30 minutes. I hope that Committee members will recognize that this is insufficient time, especially since public comment may reflect the varied opinions we have about the List. My own opinion on the High Priority List is here.

NIH Funding – As I said last week, NIH funding for ME/CFS research fell by more than 20% in 2012. Dr. Susan Maier is on the agenda for Thursday, and I am eager to hear what she has to say about the drop. I hope that CFSAC members will press for an explanation and for real change.

Case Definition – Last October, CFSAC recommended that the Secretary “promptly convene (by 12/31/12 or as soon as possible thereafter) at least one stakeholders’ (ME/CFS experts, patients, advocates) workshop in consultation with CFSAC members to reach a consensus for a case definition useful for research, diagnosis and treatment of ME/CFS beginning with the 2003 Canadian Consensus Definition for discussion purposes.” Obviously, that meeting has not happened. We do know that NIH has started a case definition process, so I hope we will hear more about that. In addition, a group of advocates have asked DHHS to stop using the broken Fukuda definition and begin using the Canadian definition. Despite all of this activity, case definition is not on the agenda for the meeting. Has the Committee done any work on this since October? Will the Secretary authorize CFSAC to hold a case definition meeting? Its absence from the agenda does not bode well.

Q&A – For the first time, a combined 45 minutes has been designated for “Public Q&A.” This could be very interesting, because I know that advocates have dozens and dozens of questions for the CFSAC and ex officios at every meeting.  I have no information on how this will be conducted, but it seems likely that it will be similar to the way questions were collected at the FDA meeting. Audience members submitted questions on cards, and moderators selected questions to pose the panel. I heard a lot of grumbling after the FDA meeting that very few questions were answered, and that the tough questions were not selected. Advocates have said the same thing about CDC’s PCOCA calls. Will this be a similar procedure, or will we see something like “open mic”?

Time – The allocation of time on this agenda is very different from previous meetings. Public comment has been reduced by one hour, but 45 minutes of Q&A was added. Ex officio reports have been reduced by 30 minutes, and lunch increased by the same amount. There were 5 hours scheduled for presentations at the October 2012 meeting, but that has been cut almost in half for this meeting. The biggest change is the increase in Committee discussion time from 1 hour, 50 minutes in October 2012, to 4 hours, 15 minutes for this meeting. This change will be welcome if the Committee uses that time to explore issues in greater depth and formulate better recommendations.

 

Last year, NIH said it was undertaking a process to identify a research case definition for ME/CFS, but individuals like me were unable to get any additional information about what NIH intended. Now additional information has been made public in a February 27, 2013 letter from Assistant Secretary for Health Dr. Howard Koh to Kim McCleary of the CFIDS Association (pdf link). I’ve done some research, and I believe we need to monitor this case definition process closely.

Case definition has been the 600-pound gorilla in the room every time ME/CFS is discussed. There are five definitions currently in use (Oxford, Fukuda, Carruthers 2003, Carruthers 2011, and Jason Pediatric) and there is no consensus among researchers and policymakers on which one is the best. (This is such a complex issue, it deserves its own post.) NIH, as the largest funding source for biomedical research, can wield great influence over the definitions used by researchers. While it was a positive step to say NIH would undertake a research definition effort, there was no transparency or information available to us until now.

In his letter to Ms. McCleary, Dr. Koh said:

the [Trans-NIH] Working Group submitted a competitive application for an Evidence-based Methodology Workshop (EbMW) on ME/CFS coordinated by the NIH Office of Disease Prevention. The EbMW consists of a thorough, unbiased evidence review of the literature related to clinical research outcomes compared across case definitions and culminating in a workshop composed of experts and patients. The workshop participants and panel members will use the evidence review to evaluate the strength of evidence for case definitions with the goals of identifying the most consistent outcomes. The Working group successfully competed with proposals from other Working Groups across NIH (e.g. The NIH Pain Consortium) for funding provided by the NIH Office of Disease Prevention. The first organizational meeting for the EbMW on ME/CFS was held on February 19, 2013. (emphasis added)

It turns out that the NIH Office of Disease Prevention has a Consensus Development Program that produces, “evidence-based consensus statements addressing controversial medical issues important to researchers, healthcare providers, policymakers, patients, and the general public.” The Office of Disease Prevention provides infrastructure, funding, and coordination for the process. The process entails the following steps*:

1. A Steering Committee of ME/CFS scientific/research experts and federal partners coordinates the EbMW with logistical support from the Office of Disease Prevention.
2. A conference panel is selected. The panelists “give balanced, objective, and informed attention to the topic.” They cannot be HHS employees or have a financial or career interest in the conference topic. They may be familiar with the conference topic “but must not have published on or have a publicly stated opinion on the topic.”
3. The Agency for Healthcare Research and Quality conducts a “systematic evidence review” and produces a report for the panel members prior to the conference.
4. A two and a half day conference is held, consisting of presentations by subject matter experts, followed by discussion among the panelists, speakers and public in attendance.
5. Dr. Susan Maier told me, “ME/CFS science/research experts and patient advocate groups with scientific/research expertise will be invited to participate in the workshop; the workshop is open to the public and will be videocast and archived.”
6. The panel drafts a statement during the meeting and presents it for commentary on the third day. The final report is issued six weeks later. It is published online and in a major peer-reviewed journal.

The Office of Disease Prevention has recently followed this process for meetings on Polycystic Ovary Syndrome (conference held December 2012) and Diagnosing Gestational Diabetes Mellitus (conference held March 2013).  In scanning the materials for these two conferences, I was struck by the absence of patients or advocacy representatives on both the Steering Committees and Panels. I point this out not to raise a ruckus about it. Rather, I think we should educate ourselves about how the process has worked in other diseases, and prepare to operate within the constraints of the existing process. If EbMW never use patients as panelists, then we should accept that limitation of the method. Insisting the methodology be changed to suit us is not likely to succeed. It would be more productive to focus on extensive preparation for the public meeting, especially since there are opportunities for open discussion with the panelists and speakers.

There is no timeline for this Workshop available yet. Nor do we know the members of the Steering Committee. Much will depend on the evidence review conducted in advance of the meeting. The evidence based report prepared for the Gestational Diabetes meeting (pdf link) is more than 300 pages long, and distills thousands of scientific papers into recommendations for clinical practice. Will we have to worry about psychosocial research making its way into the evidence based report? Much will also depend on selection of the panelists. According to the Consensus Development Program’s website, those panelists “must not have published on or have a publicly stated opinion on the topic.” Who will those panelists be?

We may not be able to participate in this process until the public meeting, but I hope advocates will join me in monitoring how this evolves. I also hope NIH will be forthcoming about each step in the process. In my experience, the engagement between advocates and the government is more positive and productive when the advocates have access to accurate information. We have a lot to learn about this methodology, and we should adequately prepare to have the best possible influence on the process.

 

*My description of the conference steps is drawn from the general description of the Consensus Development Program on NIH’s website and an email from Dr. Susan Maier, Chair of the Trans-NIH ME/CFS Research Working Group. The actual process may differ from what I describe here.

 

Dr. Joan Grobstein delivered these comments to the CFS Advisory Committee at its October 3-4, 2012 meeting. She has kindly given me permission to publish them here.

Hello.  I’m Dr. Joan Grobstein.  I’m a physician.

My topic is responsibility.

Recently we’ve seen accomplished scientists honestly and courageously admit that their original findings about XMRV were mistaken.  They took responsibility for an error.  At its best, this is how science works:  form a hypothesis, test the hypothesis, revise the hypothesis.  We would like to see the same honesty and courage from scientists at CDC about the empiric definition.  The hypothesis that the empiric definition defines the same disease as either Fukuda or the Canadian definitions has been tested and found to be wrong.  Scientists at CDC must take responsibility for this error.  The original paper on XMRV in ME/CFS patients has been retracted. CDC should retract all papers using the empiric definition or, at least, rename them to indicate that they are studies of Idiopathic Chronic Fatigue and major depression, not ME or CFS.

NIH must also take responsibility:  fund studies that will clarify the definition controversy, as it did with XMRV.  Because we saw money appear quickly to study XMRV, we know that funds are available.  It’s clear that CDC’s new study about the definition is unlikely to be impartial.  They are vigorously defending their position.  During a recent phone contact with patients Dr. Unger said CDC could be “lumpers one day and splitters the next”.  This is a remarkably unscientific statement.  The scientific method demands that we rigorously define the conditions of our investigations.  Without understanding this, how can Dr. Unger be trusted to undo the harm to ME and CFS patients that the definitional conflict has caused?  Leaders at CDC must take responsibility and ensure that science done at CDC is impeccable.  There are biomarkers for Canadian-defined ME/CFS patients.  Does CDC wish to conceal that these biomarkers are not found in empiric-defined CFS patients?

Turning now to the responsibilities of the voting members of CFSAC, its staff, and its ex officio members, we’re all aware that very few recommendations made by this Committee have been implemented.

For example, CFSAC made three specific revenue-neutral recommendations  which have been ignored.  The first, from 2009, condemned the use of the empiric definition.  Despite this recommendation, CDC continues to publish studies using the empiric.  The second recommended removing the Toolkit from the CDC website.   The third recommended making IACFS/ME’s Primer widely available.  These last two recommendation were made 4 months ago.  Today, the Toolkit remains on the CDC website.  Meanwhile, CFSAC’s own website has a new link to the Toolkit and no link to the Primer.

Who’s responsible for the lack of action?  Committee members have fulfilled their responsibilities.  It says on the website they “asked” that these three things be done.  On the contrary, they are experts, and, as such, they made recommendations to the Secretary.  Yet neither the ex officio members nor the staff have apparently worked on implementation.  Dr. Koh’s comments gave no indication that he is aware of the importance of these recommendations.  In a letter to advocates explaining his refusal to meet, Dr. Koh said, “CFSAC provides a mechanism to ensure stakeholders are engaged and have the opportunities to offer input.”  Instead, it appears that CFSAC provides a mechanism to ensure stakeholders are contained and have opportunities to offer input that will be ignored.  So what is the point of CFSAC?  If it cannot accomplish these small, high impact tasks how can it accomplish what we really need:  significantly increased funding for research, better education and improved clinical care?  CFSAC costs $235,000 annually.  That sum could fund a study of natural killer cell function in Canadian-defined patients, or create a mechanism to identify an undiagnosed low-income patient, or educate a few more physicians.  I’m a taxpayer.  I’m concerned that we’re spending almost a quarter of a million dollars each year on a committee whose recommendations are routinely ignored by DHHS.

Here’s a suggestion.  Ask ex officio members to take responsibility.  Ask staff members to assign each recommendation to the agency or agencies with responsibility for implementing that recommendation.  Ask each ex officio member to report on activities to implement each recommendation at every meeting.  If nothing is happening ask for explanations from higher levels within the agencies.

We need to see progress.

 

Let’s play a game. Imagine you have a large puzzle that makes an Impressionist picture of a colorful cottage-style garden. You can put it together as long as you have the picture on the box. First you assemble the lower left corner, all lavender and yellow flowers. Another section of red roses sits somewhere in the middle. Near the upper right corner is a section of white and gray paving stones, and you also put together an area of green herbs although you are not sure where it goes yet. This puzzle will take a lot of time to solve, but with the finished image on the box you know that you’ll put it together eventually.

Now imagine the box is gone. All you have is a white/gray blob, and lavender/yellow section, the red rose section and another green blob. The rest of the pieces are all mixed up together, and while you can separate out some edge pieces and consolidate others by color, without the box you cannot even be certain what the final picture should look like. It’s frustrating, isn’t it, to have all those pieces on the table and not see how it fits together or even know for certain that you have all the pieces. That’s the feeling I got reading the American Family Physician’s article on Chronic Fatigue Syndrome: Diagnosis and Treatment. I dissected the AAFP patient information sheet on CFS in a recent post, but now I think it’s important to examine this review article by the same authors. The article attempts to present a finished picture of CFS for family practitioners, but so many pieces are missing that the paper bears little resemblance to the CFS I live with.

Generally Speaking

“Chronic Fatigue Syndrome: Diagnosis and Treatment” by Dr. Joseph Yancey and Dr. Sarah Thomas gives an overview of CFS for family physicians. They review the Oxford and Fukuda criteria, the basic lab workup recommended by CDC, and a list of exclusionary conditions. In a section on etiology of CFS, the authors quickly cover the immune system, genetics, psychosocial, adrenal system, and sleep/nutrition. Finally, the treatment section focuses on cognitive behavioral therapy (they say it works), graded exercise therapy (this works too), nonpharmacological (nothing really helps) and pharmacological treatments (these don’t work either).

In the authors’ defense, there are significant space limitations in the American Family Practitioner journal: 1,500 to 1,800 words in the case of clinical review articles like this one. There is no way to include all the information about CFS that family doctors need in such a limited space. It also appears that neither Yancey nor Thomas are CFS experts, based on the very limited information I could find online. I emailed Dr. Yancey, the corresponding author for the paper, on October 24th with a few questions but to date I have not received a response.

Method Madness

Drs. Yancey and Thomas describe their research methods as follows:

A PubMed search was completed using the MeSH term chronic fatigue syndrome. The search included randomized controlled trials and clinical trials in English from the past 10 years. We also searched the Cochrane database, Essential Evidence Plus, the National Institutes for Health and Clinical Excellence guidelines, and the Centers for Disease Control and Prevention Web site. Search date: August 26, 2011.

This methodology accounts for some of the missing pieces. First, anything published after August 26, 2011 was not captured in the search. That includes the IACFS/ME Primer, NCI’s paper on the risk of cancer among elderly CFS patients, the ME-ICC criteria, and the Rituximab trial. But before we forgive the authors’ oversight of these papers based on the date of their literature search, consider a curiosity I found in the paper references. The authors cite one paper published after August 26, 2011: The FITNET trial of internet based CBT for adolescents with CFS is included as reference Number 27. Does that strike you as odd? If the authors truly limited themselves to the references found on August 26, 2011 then this paper should not be included. Furthermore, of all the papers published after August 2011 to include in a review of CFS treatment and diagnosis, why was a CBT paper the one cherry-picked by the authors?

Even within the boundaries of the search methodology, the authors missed some papers that would have been helpful in their overview sketch of CFS. I attempted to recreate the authors’ search in PubMed, and found more than 1,300 clinical study papers alone. These include all of the letters critical of the PACE study and Tom Kindlon’s many letters and papers on the potential harms and inaccuracies in CBT/GET studies. Other important papers such as the spinal fluid proteome by Schutzer, et al., the differential gene expression post-exercise paper from Light, et al., and the cytokine network modeling by Broderick, et al. were captured in the PubMed search but did not make it into this review paper.

Finally, there are several seminal papers that are not returned in the PubMed search. The Journal of Chronic Fatigue Syndrome published the Canadian Consensus Criteria by Caruthers, et al., in 2003. This case definition is gaining broad acceptance among policy makers and researchers, but it does not show up in a PubMed search because the journal was never indexed in Medline. Another example is the Van Ness, et al. study showing the significance of two-day exercise testing in differentiating CFS patients from controls. This is a critical paper, suggesting a possible diagnostic test (albeit an extremely unpleasant one) for CFS. But because the journal was never indexed, these papers do not show up in a PubMed search and so non-experts like Yancey and Thomas never see them.

Cognitive Bias

I do not know what Dr. Yancey and Dr. Thomas believe about CFS, including whether they believe the illness is primarily psychological in origin. After reading this paper, however, I fear this may be the case. I can best illustrate this through examples.

In the opening paragraph of the article, the authors say “CFS is often mentally and emotionally debilitating, and persons with this diagnosis are twice as likely to be unemployed as persons with fatigue who do not meet formal criteria for CFS.” What about physically debilitating? If the authors recognized the physical disability experienced by many CFS patients, and the physical suffering of all of us, wouldn’t they mention it in this paragraph? This simple omission is a very subtle way to communicate that people with CFS are not physically ill.

There is a brief discussion of the case definition in the paper. According to the authors, the 1988 CDC definition focused on physical symptoms, and the 1991 Oxford definition “emphasize mental fatigue over physical symptoms.” But the criteria, printed as Table 1 in the article, require fatigue to be “severe, disabling, and affects physical and mental functioning.” I’m no fan of the Oxford definition, but even I can see the requirement of physical disability. Again, Yancey and Thomas gloss right over the fact that CFS has serious, physical symptoms.

In discussing the biopsychosocial model of CFS etiology, the authors say: “CFS is often associated with depression, which has led many physicians to believe that CFS is a purely psychosomatic illness. Evidence supporting this conclusion is lacking.” Fair enough. But then they say, “Strong evidence suggests that childhood trauma increases the risk of CFS by as much as sixfold.” Sigh. I covered this in my dissection of the patient information sheet. Childhood trauma may have physical systemic affects, but I am not aware of any evidence showing that CFS patients have higher rates of trauma compared to patients with other illnesses like MS or lupus or diabetes or cancer. In my opinion, it is misleading to single out childhood trauma as a risk factor for CFS in the absence of such evidence.

The authors devote space and attention to CBT and GET studies, and this is understandable given the fact that CBT and GET treatments have received the most study in CFS. CBT “can help persons with CFS recognize how their fears of activity lead to behaviors that ultimately cause them to feel more fatigued and disabled.” It is true that CBT can help patients correct activity avoidance behavior, but in my experience this is a very small minority of patients. Even the CDC, target of so much criticism, does not describe CBT this way. The CDC says: “CBT can be useful by helping them pace themselves and avoid the push-crash cycle in which a person does too much, crashes, rests, starts to feel a little better, and then does too much once again.” This is a more appropriate description of CBT that acknowledges the importance of self-management and the prevalence of the push-crash cycle, as opposed to the activity avoidance highlighted by Yancey and Thomas.

Graded exercise therapy is very controversial for CFS patients, mainly because traditional GET uses a scheduled increase process as opposed to a patient-driven increase process based on symptoms. Not surprisingly, this issue is not discussed in the paper. The authors do mention that a heart rate monitor can be used to avoid overexertion during exercise, but there is no mention of the body of evidence on CFS exercise testing and pacing methods. They even cite a study that suggests improvements in GET do not correlate with increases in exercise capacity, suggesting that GET may actually work by “decreasing symptom-focusing behavior in persons with CFS.” Pacing, the only behavioral technique that truly helps CFS patients, is not mentioned by name, although the authors do say:

Patients should be encouraged to take rest periods as necessary, and to practice relaxation techniques. Although there is no evidence these modalities are effective, they are unlikely to be harmful and may be helpful.

Neither CBT nor GET is curative because it does not target the underlying mechanism of illness. CBT is not curative for cancer or heart disease either, for the same reason. Drawing the conclusion that these therapies are not curative because of the patient is a fallacy, but this is the conclusion that Yancey and Thomas suggest:

Despite the positive results of CBT and graded exercise therapy, the effects are usually moderate and rarely lead to resolution of CFS. Patients with poor social adjustment, a strong belief in an organic cause for fatigue, or some sort of sickness benefit (i.e. financial incentive) tend to have worse responses to therapy. Unlike with many other illnesses, membership in a CFS support group was associated with worse outcomes.

The study cited by the authors in support of these statements is this one from 2002. That study points out its own limitations: it uses the Oxford definition, lost 17% of the patients to follow-up, and did not actually measure the exercise capacity of the patients. But this is the kind of evidence that is sufficient for Yancey and Thomas.

The overall tone, selective quotation, and reference choices give me the impression that the authors believe CFS to be a psychological condition, at least in part. I do not know this for a fact, but if I read only this article about CFS and nothing else, I would believe that it is an emotional problem. It’s not just the amount of space devoted to the psychosocial research. The authors focus on the psychological elements to the exclusion of discussion of physical disability, post-exertional malaise, and the well-documented physiological findings in this illness.

Missing Pieces

There are huge gaps in this paper. Orthostatic intolerance, an issue for most CFS patients, is not mentioned at all. Post-exertional malaise is not explained, and no CFS exercise studies are referenced. The importance of medications and other treatments in managing sleep and pain issues is ignored, and pain is barely discussed at all.

This article illustrates a few pieces of the puzzle, mainly CBT, GET and the psychosocial model of CFS. A family physician reading only this article would not be able to separate chronic fatigue from CFS patients, and would understand almost nothing about the complexity of CFS. I found the tone to be generally hopeless: try therapy and exercise but it probably won’t help you much. Maybe a motivated physician would visit the CDC website (and this illustrates the importance of fixing problems in those materials).

No one will be able to assemble the CFS puzzle using the pieces in this article. Too much evidence is ignored, too much emphasis is placed on the psychosocial pieces, and there is very little information about how to manage the other symptoms of the illness. I know the full picture exists and I can identify the gaps. But a family physician who does not have the picture of the box will not recognize all that is missing and will never be able to assemble the pieces in a way that will help CFS patients.

I fear that doctors will rely on this article to provide the same kind of advice I received from doctors in 1994: keep going to the gym, staying in bed is the worst thing you can do, get some counseling, there is nothing else we can do to help you. This bad advice and hopelessness did not help me, and may have even hurt me by keeping me much more active than my body could tolerate. It was years before I found and received adequate care for pain, sleep, and orthostatic intolerance, and even more years before I found expert help for pacing and activity management. This article will do nothing to change the way doctors treat CFS, and will reinforce the destructive pattern already in place.

The FDA hosted a public meeting this morning to discuss the Patient Focused Drug Development (PFDD) initiative. The meeting was available via webcast, and a transcript will be published on the FDA website. CFS is on the list of candidate diseases to be included in this process, so the meeting was of great relevance to us as patients and advocates.

The goal of the Patient Focused Drug Development Initiative is to create a more systematic way for FDA to collect and use patient perspectives on the burden of disease and the risk/benefit ratio of treatments. While patient input is used in a variety of ways in the drug approval process, it is not as systematic and comprehensive as is needed. Dr. Janet Woodcock, the director of FDA’s Center for Drug Evaluation and Research, explained that FDA wants to understand patients’ perspectives on the burden of illness, how it affects daily life, how treatments affect those symptoms and outcomes, and what degree of risk is acceptable for the benefits. Every patient has a different experience of disease burden and tolerance for risk, so collecting single patient input on these questions may not capture the full spectrum of patient experience. The selection of twenty conditions (from the proposed list of thirty-nine) is intended to be a pilot program to help the FDA figure out how best to collect this input more generally.

Dr. Teresa Mullin, Director of the Office of Planning and Informatics, explained that making a determination of the balance between treatment risk and benefit requires an analysis of the condition and the current treatment options. Patients can speak to the clinical manifestations of the condition that have the most significant impact on them, as well as other aspects of the condition that affect daily life. Patients can also speak to how those impacts change with disease progression, and share their own experiences of the current standard of care and all treatments being used (including non-pharmacological treatments). While many of these issues have been considered and discussed from the clinicians’ point of view, it is very common for patients to have a very different view of the symptoms they feel most affect daily life or how well treatments work (or not) over time. Dr. Mullin said that the objective of this PFDD process is to create a systematic way to collect broad patient input and capture it in a usable and useful format to be used by review panels when considering products for approval.

In discussing why the FDA selected the thirty-nine candidate diseases, Dr. John Jenkins, Director of the Office of New Drugs, said that collective patient community input was essential throughout the approval process from the oversight of trials through post-approval safety issues. He pointed out that the patient perspective is very different from that of consumer safety advocates. For example, patients with asthma have a very different risk tolerance with inhaler medications compared to safety advocates who do not have asthma. Several division directors explained why their divisions had proposed specific diseases, including Dr. Theresa Michele from the Division of Pulmonary, Allergy and Rheumatology Products. Dr. Michelle is also FDA’s ex officio representative to the CFS Advisory Committee, and she spoke about the severity of CFS and why her division recommended its inclusion in the PFDD process.

Most of the remaining time of the meeting was devoted to hearing public comment. In an attempt to give everyone time to speak, comments were limited to two minutes but this was not enforced by the meeting moderator. Patients and advocates representing diverse conditions spoke about why their disease should be part of this process, including Alpha-1 antitrypsin deficiency, alopecia, ALS, Alzheimer’s, amyloidosis, arthritis, angioedema, Batten disease, blood cancers, brain tumors, dystonia, gastroparesis, hereditary cancers, inflammatory bowel disorders, interstitial cystitis, kidney diseases, lung diseases, melanoma, migraine,  muscular dystrophy (including Duchenne), and narcolepsy. Four members of our CFS community spoke: Mary Dimmock, Joe Landson, Amy Squires, and Mary Schweitzer.

Several things struck me during all the public testimony. First, I found it heart-breaking to listen to so much suffering. Dealing with CFS, we sometimes have blinders on and I think we forget how many other millions of people are suffering from poorly understood diseases with no treatment and no help. One man with ALS said he would celebrate if he had some of the other diagnoses on the proposed disease list, and did not understand why ALS was missing from the list. A woman with gastroparesis described her suffering in brutal detail, and drew a parallel between her experience and having the stomach flu every day. How many times have we CFS patients described our illness as having the worst influenza every day? It quickly became clear that for all the advances in medical care, there are too many diseases and too many patients and too many families suffering.

Second, a number of advocates pointed out that by selecting individual diseases, FDA had caused a “disease war,” in which groups were competing to get on the list. As an alternative, they proposed hosting PFDD meetings on body systems (lungs, nervous system, immune system, etc) or other factors (such as severity or availability of treatments). They reasoned that the combination approach would allow more diseases to be represented and capture more diverse patient input.

My personal opinion is that this would be a mistake. This is intended to be a pilot process to collect input that will be useful to drug review panels. I do not believe that a systems approach will collect the level of detail on CFS or other illnesses that is necessary for reviewers. How can a meeting on gastointestinal disorders capture a sufficient level of detail on patients with Crohn’s disease and gastropareisis that can be used in the drug approval process for a treatment for only one condition? And what about diseases like CFS and amyloidosis that do not have a single body system “home”? I believe FDA needs to drill down to a fine level of detail in collecting and understanding patient perspectives, so I hope they will not start combining conditions in an effort to cram more disease groups into these meetings.

Your input is necessary now! The public docket to submit comments on the disease list closes on November 1st. If you can, please write to FDA and give your perspective on how CFS meets the following criteria:

• Disease areas that are chronic, symptomatic, or affect functioning and activities of daily living;
• Disease areas that reflect a range of severity;
• Disease areas for which aspects of the disease are not formally captured in clinical trials;
• Disease areas that have a severe impact on identifiable subpopulations (such as children or the elderly);
• Disease areas that represent a broad range in terms of size of the affected population
• Disease areas for which there are currently no therapies or very few therapies, or the available therapies do not directly affect how a patient feels, functions, or survives.

FDA will take several months to review the collected input and decide upon the first twelve diseases for PFDD meetings in 2013 through 2015.

I’m on the verge of tearing my hair out, and I suspect I’m not the only one. The American Academy of Family Physicians published a review article about CFS (paywall) on Monday, accompanied by a patient information sheet. From the very first sentence, this information sheet is a disaster. It packages harmful misinformation for family doctors to share with patients. Let’s take a look:

Chronic fatigue syndrome (CFS) is a disorder that causes you to be very tired.

NO! No it does not! A person with sleep apnea is tired. A nursing mother is tired. A perfectly healthy person studying for the bar exam is tired (ask me how I know). CFS does not make me tired. CFS causes prostration, a medical term that means a collapse from complete physical or mental exhaustion. Using the word “tired” is not only medically inaccurate, it falsely minimizes the severity of my disease and my experience.

People with CFS may have other symptoms, such as poor sleep, trouble with remembering things, pain, sore throat, tender lymph nodes, or headaches.

Can you spot what’s missing? Post-exertional malaise! The generally accepted hallmark symptom of this disease is not on the list. It is the first symptom on the Fukuda criteria list of accompanying symptoms. But it’s not listed here and not explained to the patient.

Not everyone with CFS has all of these symptoms.

I know hundreds of CFS patients. Every single one of us has experienced these symptoms for extended periods of time, if not daily, over the course of years. While it is technically correct that the Fukuda criteria do not require all of those symptoms, it is an oversimplification to simply say we don’t have all the symptoms. And of course all the other symptoms and overlapping conditions are not mentioned at all.

Childhood trauma (for example, physical or sexual abuse) may raise the risk of getting it.

I am aware of two studies that showed a higher prevalence of childhood trauma among CFS cases compared to healthy controls (this one and this one). Here’s the problem: childhood trauma may raise the risk of many disorders later in life. Without comparing the prevalence rate of trauma among other illness groups, there is no way to know if the association with CFS is unique. Are there studies comparing the incidence of childhood trauma among people who develop multiple sclerosis, rheumatoid arthritis, cancer, hepatitis, heart disease or  . . . oh, that’s right. Doing that kind of study in those illnesses might be offensive because those illnesses are real. But we can do those studies in CFS with no problem.

Two treatments can help with CFS: cognitive behavior therapy (CBT) and graded exercise therapy. With CBT, a therapist teaches you about how your thinking affects how you feel and act. With graded exercise therapy, you slowly increase your physical activity, which hopefully increases your function.

You know where this is going, right? Setting aside the arguments about whether CBT and GET studies actually show a benefit, and setting aside how this sort of statement plays right into the mental illness meme, let’s talk about GET. Will GET increase CFS patients’ functional ability? Maybe some patients, but it should be pursued with extreme caution and prejudice. As the work of the Pacific Fatigue Lab and my own exercise testing results show, the energy metabolism systems of CFS patients are severely impaired. We do not make or use energy, or recover from activity, the way other people (including other illness groups) do. Graded exercise must be undertaken very carefully because it takes very little activity to push a patient into a severe crash.

I shudder to think about how family doctors will use this information sheet, and what it will do to the patients who receive it. What is truly remarkable about it is that it bears only a passing resemblance to the full review article and the AAFP’s patient education page on CFS. But this watered down, oversimplified summary of misinformation about CFS will undoubtedly be used, and it is likely to make things worse for patients, not better.

So does anyone – journalists, doctors, policymakers, or other observers – wonder why the CFS Advisory Committee and patient advocates have been begging CDC to fully revise its website and remove the harmful content that filtered into this information sheet?

This is why.

Does anyone wonder why the CFSAC  recommended that the CDC remove its Toolkit from the CDC website?

This is why.

Does anyone wonder why an alliance of organizations and patients wrote a lengthy and heavily referenced position paper in support of that recommendation?

This is why.

Does anyone wonder why there was such vigorous disagreement at the CFSAC meeting about whether professional societies like the AAFP should be invited to participate in revising the CFS case definition?

THIS. IS. WHY.

 

 

Update November 2, 2012: Author Toni Bernhard published a great article about the AAFP patient information sheet.

Update October 31, 2012: I’ve also published a detailed analysis of the AAFP review article on CFS.

The CFS Advisory Committee held its second meeting of the year on October 3-4, 2012. Last time, I organized my summary around the good, the bad, and the WTF moments. This time, I am organizing around the discussion themes. Overall, I felt this meeting was more substantive than in the past. There were even hints of introspection and data driven discussion.

Agency Updates

Assistant Secretary Dr. Howard Koh attended the opening of the meeting, and provided an update on the Department’s efforts since the last meeting. I was watching the meeting via webcast, and my feed froze during Dr. Koh’s comments. However, the portion I did see contained nothing new. Dr. Koh did not provide any details on the Ad Hoc Working Group beyond what we already know. Unlike previous meetings, he did not take questions from the members. Although he said “the committee has gotten stronger,” he did not announce the appointment of a new member to replace Dr. Rose. The committee bylaws require vacancies to be filled within 90 days, so the failure to appoint a replacement is a violation of the bylaws.

Both the FDA and Social Security Administration gave substantive presentations to the Committee. In my opinion, this was the high point of the meeting. Both Dr. Sandra Kweder (FDA) and Arthur Spencer (SSA) provided detailed information about their agencies and CFS related data. Dr. Kweder reported on the status of nine investigative new drug applications for CFS. Mr. Spencer provided disability data that the committee has been requesting for years. The overall approval rate for Social Security disability among cases where CFS is the primary diagnosis is 21%, in contrast to a national overall rate of 30%. I’m looking forward to seeing the slides from both these presentations because there was a lot of good information in them.

NIH and CDC also gave detailed updates. Dr. Susan Maier (NIH) reported that several new members were added to the Trans-NIH ME/CFS Working Group, including Dr. Harvey Alter. It’s very good news that Dr. Alter is staying involved in CFS despite the end of XMRV. Dr. Maier also provided (for the first time) data on the acceptance rates for CFS-related grant applications. The overall success rate is 25%, and in FY2012 the success rate is 18%. These rates are higher than the overall rate across NIH. Most of CDC’s report was focused on various education initiatives including CMEs offered through Medscape and CDC, as well as video of patient vignettes for the MedEd Portal that will be finished next year.

That ToolKit

CDC announced that after extensive debate, they have decided not to remove the ToolKit from the CDC’s website. Dr. Beth Unger said that they believe it should be available until it can be updated to reflect the other website revisions. Surprisingly there was little fanfare or reaction to this announcement. At its June meeting, the CFSAC had recommended that the ToolKit be removed. Dozens of patients testified in June and at this meeting that the ToolKit is harmful misinformation, and a coalition of groups and individuals submitted a detailed position paper to CDC in support of that June recommendation. Despite all that, the CDC has decided to keep the ToolKit. There was no pressure or reaction on the record from CFSAC members. No one asked why this decision was made, and no one besides Mr. Steve Krafchick pointed out that CDC is ignoring the CFSAC recommendation. CDC got off very lightly on this score, and I still can’t believe that no one raised a stink about it.

Chicken, Meet Egg

As I said above, Dr. Maier presented data on the approval rates for CFS applications to NIH. In light of that data, Dr. Gailen Marshall asked the committee why they thought NIH funding was so low. The high approval rate suggests that the problem is not NIH’s willingness to spend money but that there are few applications coming in. Dr. Mary Ann Fletcher spoke frankly about the perception in the research community that it is extremely difficult to get funding. She cited an unnamed researcher who left the field because of it, and pointed out that Dr. Nancy Klimas is quite successful in her applications for HIV and Gulf War Illness funding but not CFS. Eileen Holderman pointed out that the illness name, and particularly CDC’s definition and use of the name, dilutes our disease into simple chronic fatigue. This discussion tied in nicely with public comment by Matthew Lazell-Fairman and others that the decades of neglect and active denigration of the disease by CDC and other federal policy makers has created the climate where researchers believe they will not get funding. This circular discussion recurs at every single CFSAC meeting, but this time it led to the recommendation of creating a CFS study section at NIH.

Biomarkers

Biomarkers in CFS was a recurring theme on both days of the meeting. Dr. Jordan Dimitrikoff gave a presentation on the challenges faced by those studying Chronic Pelvic Pain Syndrome to identify biomarkers, not just for diagnosis but also to generate hypotheses about potential treatments. This is very similar to the approach of several CFIDS Association grants, in which a symptom or biomarker is queried to identify a possible drug to address that symptom or marker. Dr. Dimitrikoff acknowledged that the “true experts are the patients,” and he advocated setting aside cognitive bias to evaluate data and create learning networks. Dr. Fletcher then presented data from her research with Dr. Klimas and Dr. Gordon Broderick which identified different gene expression profile networks in CFS and Gulf War Illness patients, especially in immune pathways. This presentation complemented Dr. Dimitrikoff’s nicely, giving very specific examples of how biomarkers could lead to identifying potential drug treatments.

Discussion covered several very important points. First, that the case definitions are producing too much variability among patients. Without animal models, it is very difficult to study patients in a meaningful way without narrowing down the clinical presentation. Second, biomarkers must be distinctive in order to be useful. It is not enough to distinguish healthy controls from CFS patients. Biomarkers must distinguish between CFS and other chronic inflammatory conditions. In other words, if a biomarker cannot distinguish CFS from rheumatoid arthritis or lupus then it is of less utility than one that can. This has implications for both diagnosis and treatment trials.

Dr. Kweder’s presentation on the FDA and CFS treatment trials focused on the importance of outcome measures in order to quantify whether a treatment is having an effect. Outcome measures are not necessarily biomarkers; for example, there is no biomarker for migraines. But the more objective and quantifiable an outcome measure is, the more useful it is in clinical trials. Dr. Kweder pointed out that CFS has no single accepted case definition, no quantifiable way to measure symptoms and no biomarker for disease presence or activity. These are barriers to clinical trials, and partially to blame for the lack of trials in CFS. Dr. Kweder cited fibromyalgia, irritable bowel syndrome and depression as examples of conditions that received more clinical trials when those barriers were addressed. The FDA stakeholders’ meeting in spring 2013 will focus on identifying valid reliable outcome measures for CFS clinical trials.

There is a significant difference of opinion about whether we already have biomarkers and outcome measures for CFS. Dr. Fletcher and others cited a variety of measures already in use by researchers and clinicians. Dr. Fletcher was adamant that biomarkers did not need to be exclusive to CFS in order to be useful. Dr. Kweder said that a quantifiable biomarker or outcome measure must correlate to how the patient feels or fares. She also noted that heterogeneous conditions need larger clinical trials, so identifying subgroups can help target a treatment to those it is most like to help.

Case Definition

This is such a controversial topic, perhaps I should not expect a discussion of it to go smoothly, but the committee struggled once again to chart a way forward. Dr. Nancy Lee said that the case definition issue was discussed in at least one meeting with Secretary Sebelius, and that the Secretary was clear that the case definition must come from the medical community. Dr. Lee said that a recommendation from the committee that the Secretary endorse or adopt a specific definition will go nowhere. Dr. Marshall tried to focus discussion on designing a process that would produce a definition, but the committee quickly got snarled in the complexity of the problem.

One of the most contentious issues was whether the medical community has already endorsed a definition. Mr. Krafchick pointed out that the IACFS/ME used the 2003 Canadian Consensus Criteria in writing the Primer, and that it was the body of experts in this condition. Dr. Lee argued that the entirety of the medical community needed to endorse a definition, and Dr. Fletcher countered that this was not only unrealistic but was not a standard applied to any other illness. The root of this disagreement is the status of the IACFS/ME versus other medical societies. When the American College of Rheumatology endorsed a definition of fibromyalgia, the rest of the medical community accepted it because the ACR is a defined sub-specialty of medicine. Dr. Marshall drew a sharp distinction with the IACFS/ME, which is not a sub-specialty that offers board certification, and insisted that the American Colleges must have input into the definition in order for it to be widely accepted. This led to another vigorous argument over whether ME/CFS experts should address the definition or if non-experts should be invited to provide input and endorsement. The committee split over this, and in the end voted 5-4 (with one abstention) in favor of limiting input to the ME/CFS experts at this stage.

The other thorny question was whether to start with one of the existing definitions (Fukuda v. Canadian Consensus 2003 v. International Consensus 2011 – and different members referred to these papers by different names which made it even more confusing) or start from scratch. Dr. Dimitrikoff and Dr. Dane Cook recommended learning from definition processes in other illnesses such as lupus or IBS. Dr. Ermias Belay and Dr. Unger from CDC both advocated for a data driven process, relying on their multisite study that should be completed next year (although they did not promise a finished paper next year). This led to frustration among Dr. Fletcher, Mr. Krafchick and others about delay and the need for immediate action and leadership. After much wrangling, the committee settled on the 2003 Canadian Consensus Criteria as the starting point for a process to produce a clinical definition (see text of recommendation below).

One thing that got lost in this discussion was the role of patients. My impression from the preliminary discussion on October 3rd was that Dr. Marshall and others recognized patients as important stakeholders in this process. But the role of patients was not discussed on October 4th,  and the final text of the recommendation did not specifically include or exclude us. I don’t think it is an exaggeration to say that there will be hell to pay if patients are excluded from the process of creating a new case definition.

Committee Effectiveness

At the end of the first day, Dr. Marshall invited committee discussion on recommendations or other issues for the next day’s session. This led to a discussion of how effective the Committee is in its work. Dr. Lisa Corbin and Mr. Krafchick expressed concern about the committee’s recommendations not receiving feedback or action. Dr. Lee stated that a response to the June recommendations is still in preparation, to which Mr. Krafchick noted that 111 days had passed since that meeting. It was also clear, once again, that members are not receiving materials related to the meetings. Dr. Krafchick had not seen Assistant Secretary Koh’s letter in response to the November 2011 meeting, and was told that “it’s on the website.” Does this mean that such key documents are not sent to members, or that they are not even notified when such information is posted to the website? Members were asked to read several articles in preparation for the case definition discussion the next day (again suggesting that they were not sent in advance), but the existing CFS case definitions were not among them. To be frank, I think it is appalling that more preparation is not done for these meetings and it clearly hampers the effectiveness of discussion. I also wish that members would give more thought to the phrasing of their recommendations in advance. The editing-by-committee process at the end of each meeting is frustrating to watch, and a little more care in proposing motions might help with that.

Final Recommendations

These are the recommendations to the extent I was able to capture the language. The final version may vary slightly:

1. CFSAC recommends that the Secretary promptly (before 12/31/12 or as soon thereafter as possible) and in consultation with CFSAC members convene at least one stakeholders (ME/CFS experts) meeting to examine the Canadian Consensus case definition (Carruthers, 2003) and its utility for diagnosis and treatment of ME/CFS.
2. CFSAC recommends that there be a standing committee for review of ME/CFS proposals at NIH.
3. CFSAC recommends that NIH issue an RFA of $7 to 10 million to establish outcome measures, including but not limited to biomarker discovery and validation, in ME/CFS patients. (Note: This replaced a recommendation limited to just biomarker discovery and validation passed by the committee during the same discussion.)
4. CFSAC recommends to the Secretary that she endorse the Coalition 4 ME/CFS option 1 proposal for the ICD10-CM that was recommended at the 9/19/12 NCHS public meeting. (Note: The committee passed this recommendation despite advice from Dr. Nancy Lee (DFO) that the Secretary would not intervene in the ICD10-CM process.)
5. CFSAC recommends that the Secretary allocate specific funds to study cluster outbreaks of ME/CFS.
6. CFSAC recommends that the Secretary allocate funds to study the epidemiology of patients with severe ME/CFS.
7. The members also voted unanimously to send a thank you letter to President Obama.

After three years of controversy about the purported association between CFS and XMRV, and after two years of waiting for the definitive Lipkin study to be finished (full text of the paper is here), we have our answer. Stick a fork in it, people, because XMRV is done. There are plenty of places to get summaries (such as here and here and here, and a quite revealing interview with Dr. Lipkin here). I want to focus my analysis on the issues that come up the most in patients’ discussions about XMRV.

Did the Lipkin study use the right patients? As far as I can tell, yes. The Lipkin study used the Fukuda and Canadian Consensus Criteria, and only selected patients that had a sudden viral-like onset. Dr. Lipkin said today that this was done so that they chose subjects with a high likelihood of having an infection. The patients were selected by six clinicians around the country (to avoid any limitations based on geography): Dr. Cindy Bateman, Dr. Nancy Klimas, Dr. Anthony Komaroff, Dr. Susan Levine, Dr. Jose Montoya, and Dr. Dan Peterson. If you know anything about CFS, then you recognize these clinicians’ names. Cases were further examined for exclusionary conditions, like hepatitis, HIV, and thyroid dysfunction. Again, this was done to avoid confounding the results by introducing too many variables. Finally, cases had to demonstrate a required level of functional impairment based on responses to four clinical questionnaires. By comparison, the patients in the original Lombardi study met both the Fukuda and Canadian criteria, and presented with severe disability (Lombardi Supplemental). Those samples came from the Whittemore Peterson Institute’s national tissue repository (Lombardi), included samples from geographical diverse areas and included some cluster outbreaks. The Lombardi paper does not specify whether testing was done to exclude other infections, how long the samples had been stored prior to use in the study, or the mean length of illness. The Lipkin study appears to have done everything possible to identify a clean cohort of severely ill CFS patients who were likely to have evidence of infection, and we have much more information about this cohort than we do about the original Lombardi cohort.

Why not test the same patients as Lombardi, et. al? That’s been done. The Singh  and Levy studies both retested reported positives from WPI. The Blood Working Group study also used reported positives from WPI and Lo, et al. Those studies were all negative. Dr. Lipkin did not explicitly address this issue in the press conference, but I assume that the point was to start with a fresh cohort and try to replicate the association between these viruses and CFS.

Were the samples handled correctly? As far as I can tell, yes. Dr. Lipkin spent significant time at the press conference this morning addressing the issue of why blood was used in this study. This is important, because after the negative replication attempts began to pile up, XMRV-theory supporters began claiming that the virus could not be detected in blood, but could be found in tissues. The question was raised again this morning by both Hillary Johnson and Deborah Waroff. Dr. Lipkin and Dr. Alter both said that the reason blood was used in this study is because both the Lombardi and Lo studies found XMRV/pMLVs in blood. I’m not sure why this gets lost in discussions about XMRV. The Lombardi paper found XMRV in 67% of the CFS blood samples they analyzed. It wasn’t tissue; it wasn’t lymph; it was blood. So an attempt to confirm the Lombardi and Lo findings has to look at the blood.

For the Lipkin study, blood was drawn fresh from patients and controls between 10am and 2pm, within the same season (to control for possible communal infections and diurnal variations).  The blood was treated with EDTA (an anticoagulant) and shipped overnight to Columbia University where the coding and sample splitting was done. The Lombardi Supplemental says that blood samples were treated with sodium heparin, a different anticoagulant. There is no information provided about the time of day or time of year that samples were collected, nor the length of time samples were stored before the study. I’ve seen some claims online that the type of anticoagulant used makes a difference, but I have no information to say for sure either way.

After coding, each sample in the Lipkin study was divided into multiple aliquots. There were four testing sites (more on this in the next section): CDC, FDA, Dr. Hanson’s lab at Cornell, and Dr. Ruscetti’s lab at NIH. Each group received a double set of samples – 2 each of every patient and control. In addition, the groups received artificially spiked positive controls and known negative controls.

Did they use the right tests? Yes. Each of the four testing sites used their own assays in the Lipkin study. CDC used assays previously described in earlier papers to perform multiple rounds of PCR. FDA used a modified version of the assays described in the Lo paper to run PCR. Dr. Hanson performed PCR on samples that had first been cultured in the Ruscetti lab. Finally, the Ruscetti lab used a serologic assay that was slightly modified from what had been reported in Lombardi. Each lab used both negative and positive controls and got accurate results with those samples.  Is it a weakness that these labs did not use the precise assays used in Lombardi and Lo? I suppose one could make that argument, but the flip side is that refinements in testing should be used to produce (hopefully) better results. If the labs had been required to use the exact tests used in Lombardi, and the results were negative, it would be a fair question why they were prevented from applying what had been learned since Lombardi. With this design, each lab could use the technique that it felt was most likely to produce accurate results.

Were the positive/negative results reliable? Yes. The Lipkin study testing involved PCR of plasma, PCR of PBMCs, PCR of cultured PBMCs, and serology testing. Remember that each subject sample was not only split among the labs (so subject x was tested by each group), but each sample was sent to each location twice (so subject x was tested twice by lab A, twice by lab B, etc). In order to be counted as a positive result, the Lipkin study states: “Subjects with two positive results in the same sample type were considered positive for XMRV/pMLV.” In other words, subject x had to test positive in two plasma samples or two PBMC samples, etc. to be counted positive. The original Lombardi and Lo studies did not use this redundancy.

The results were clear: No positives were found by CDC in plasma. No positives were found by FDA in plasma or PBMCs. No positives were found by Hanson in cultured PBMCs. (Lipkin study Table 3).  Zero, zip, nada, nyet, nothing. Why do they think that PCR is reliable? Because Lombardi used PCR. This is another fact that has frequently been forgotten or swept under the rug during online discussions of XMRV. People have been claiming that you can’t find XMRV with PCR, when the original study used PCR. The Lipkin study included positive and negative controls, checks for contamination, and PCR found NOTHING (except in the positive controls).

The serology results were not clear cut. Approximately 6% of both the patients and the controls were found to be positive using a slightly modified version of the serology assay used in Lombardi. However, the Lipkin study points out that this antibody cannot be validated in a sample known to be positive for clinical XMRV infection, since there is no confirmed case of human XMRV infection. Furthermore, the antibody used may be cross-reactive, meaning it appears positive in the case of a non-XMRV infection. The CFIDS Association article on the study explains this nicely. In the paper, the authors state, “We posit that positive results represent either nonspecific or cross-reactive binding.” The fact that the same number of positives were found in both patients and controls is strongly suggestive that the result is not associated with CFS. In his interview with Nature, Dr. Lipkin said, “If you consider this in the context of the work that shows that XMRV originates in the laboratory, then I think we can probably close the door on this once and for all.”

The consensus reached by all of the study authors could not be clearer: “Our results definitively indicate that there is no relationship between CFS/ME and infection with either XMRV or pMLV.”

Where do we go from here? The Lipkin study ends as follows:

We remain committed to investigating the pathogenesis of CFS/ME and to ensuring that the focus on this complex syndrome is maintained. Studies under way include the search for known and novel pathogens and biomarkers through deep sequencing and proteomics.

There was much discussion at the press conference about the promising avenues for further inquiry, including additional pathogen discovery work, examining host response, and looking at protein and gene products. Dr. Lipkin is involved in some of that work through the Chronic Fatigue Institute. In his interview on This Week in Virology, Dr. Lipkin also said that he is professionally invested in the search for the pathogenesis of CFS.

Much was also made of the fact that the samples gathered for the Lipkin study represent an extraordinary resource for future research. The samples are stored in freezers at NIH and are available for qualified investigators. Application to use these samples must be made through NIH, and Dr. Lipkin stated that two investigators had already received samples and were working on them (although he offered no more specific information). In the TWiV interview, Dr. Lipkin said that it was the panel of investigators on this study that approved applicants for samples, but he didn’t explain how that works. He also said that there would be NIH money available for an RFA to use the samples, but this is the first I heard that. Obviously, an RFA from NIH with money attached would be big news and tremendous progress – so I hope we can get that confirmed by NIH. Finally, he said there is enough plasma stored for 50 labs to conduct studies. I think this is a huge positive outcome; more money was spent on this study by NIH than for any other CFS study in 2011. I am thrilled at the prospect that we might learn more from these samples.

Is XMRV really over? Yes. On top of the definitive statement in the paper, Dr. Mikovits and Dr. Alter firmly closed the door on XMRV/pMLV and CFS today. Dr. Alter said this study was “quite definitive.” Dr. Mikovits said the study rigorously excluded the earlier findings and that XMRV is “simply not there.” Furthermore, she said she was “100% confident in the results.” It can’t be said any plainer than that. Dr. Mikovits is on record as denying an association between XMRV/pMLVs and CFS. I’m fairly certain there will be some people who are still not convinced, but they will have to make their claims in spite of what Dr. Mikovits said herself.

What about the prostate cancer papers? That’s done, too. A study published today in PlosOne today concludes “In summary, our findings do not support any association between XMRV infection and prostate cancer, and by extension indicate that XMRV has never replicated outside of the laboratory setting. The initial discovery linking XMRV to prostate cancer in 2006 arose from laboratory contamination of clinical samples by an XMRV-infected LNCaP cell line. In turn, the LNCaP cells were most likely previously infected by 22Rv1, from which XMRV almost certainly originated through in vivo passaging of the CWR22 xenograft in mice.” Update at 8:10 pm: the original XMRV and prostate cancer study from 2006 is now retracted.

 

I am going to refrain from any comment on the XMRV study results announced today until I have had a chance to read the paper, listen to the press conference, and think about the whole thing for a few hours. In the mean time, here are some related materials:

• Two European news outlets broke the embargo by more than three hours with disappointingly simplistic summaries (at least one article was subsequently withdrawn)
• The Lipkin study results published in mBio today
• The link for the Lipkin press conference at 10:30 am Eastern
• The link to the This Week in Virology podcast interview with Dr. Lipkin (updated at 12:07 pm to add link)
• Press release from Dr. Lipkin’s Center for Infection and Immunity (pdf)
• The CFIDS Association summary of the paper (updated at 9:42 am to add link)
• Statement from the ME Association asking for an apology to patients
• My post on the history of the Lipkin study