Occupy CFS

NIH spending on ME/CFS research has been controversial since I’ve been in advocacy, largely because the funding numbers are so low compared to the burden of this disease on people and the economy. I’ve examined the details of spending in previous years, including an analysis of 2011. The 2012 numbers are now available, and the news is not good at all: funding has fallen off a cliff to its lowest level since 2008.

First, recall that NIH had projected to spend $6 million on CFS research in 2012, the same as the amount spent in 2011. Unfortunately, NIH now says that it spent $5 million in 2012, and projects the same amount for 2013 and 2014. Even worse, when I dug into the actual grants, I found that NIH had spent far less than $5 million.

There are 16 grants listed for 2012 spending (several grants appear twice on the list because they received funding from more than one Institute) for a total of $4,518,182. This is a decrease of $1,827,966 or 28.8% from the 2011 funding. In 2011, ME/CFS was 218th out of 235 disease categories funded by NIH. In 2012, we dropped to 224th place.

Unrelated Grants

To make it worse, three of the grants NIH included in the 2012 ME/CFS list are not actually related to ME/CFS:

• A grant to Dr. Matthew Hayes for $80,000 is investigating the potential mechanisms that cause nausea and malaise after the administration of a class of drugs for diabetes in the hope of developing treatments for obesity. I have no idea why this is categorized as CFS-related, unless it was the use of the word “malaise.”
• Two grants relate to XMRV, and as such should also be excluded as non-CFS related. NIH’s own study on XMRV (the Lipkin study) established that XMRV is not found in CFS patients or controls, and the original Science paper was retracted in December 2011. There is no reason to allocate XMRV spending to CFS research. Dr. Monica Roth received $293,436 as part of her ongoing study in the integration of murine retroviral vectors. Dr. Jeffrey Cohen received $448,678 in a new intramural NIH study that did not detect XMRV in CFS patients or patients with other chronic inflammatory diseases, and also tested use of a particular drug in a person with herpesvirus infection – although that patient does not appear to have CFS.

These three grants account for $822,114 or 18% of the total NIH claims to have spent on ME/CFS. Obviously, less than $1 million is not much in research terms, but for our field it is a huge amount.

Category Breakdown

After excluding the three unrelated grants, we are left with thirteen grants for a combined total of $3,696,068. Let’s see how they break down by category:

• Two studies tested psychological treatments. Dr. Fred Friedberg received $368,424 for his ongoing study of home-based illness self-management. Dr. Michael Antoni received $541,505 for his study of telephone based patient-partner cognitive behavioral stress management.
• In the area of orthostatic intolerance, Dr. Anthony Ocon received $47,232 to continue his study of nitric oxide and orthostatic intolerance in CFS patients. Dr. Dikoma Shungu received $269,536 for a treatment study of an amino acid and its impact on oxidative stress. Dr. Shungu’s grant was a new award in 2012 (and is distinct from his $2 million grant announced in March 2013).
• Two new grants will look at the role of the gut microbiome in CFS, with Dr. Maureen Hanson receiving $227,220 and Dr. Mary Ann Fletcher receiving $181,621. Both of these grants were new awards in 2012.
• The remaining grants investigate neurological, endocrine, or immune aspects of ME/CFS for a total of $2,060,530. The grants to Dr. Nancy Klimas, Dr. Theoharis Theoharides, Dr. Vincent Lombardi, Dr. Benjamin Natelson, Dr. Kathleen Light, and Dr. Leorey Saligan are all continuations of grants funded in 2011. Only one grant is new: Dr. Roland Staud will investigate the peripheral and central mechanisms of fatigue and pain through specific receptor cells in muscles in patients with ME/CFS.

So how does this stack up against prior years? Not very well.

	2008	2009	2010	2011	2012
Total spending	$3,503,942	$4,844,044	$6,194,042	$6,346,148	$4,518,182
Not CFS Related	9.3%	7%	6.5%	0	1.77%
XMRV	0	15%	29.3%	27.5%	16.43%
Psychological	21.3%	12%	12.3%	13.5%	20.14%
Orthostatic intolerance	33%	25%	13.5%	13.5%	7.01%
Neuroendocrine Immune	36.3%	42%	38.3%	45.5%	54.65%

As you can see, the 2012 spending is the lowest total amount since 2008. Orthostatic intolerance research is at its lowest point in five years, and psychological research is at its highest percentage since 2008. The only good news is that for the first time in five years, neurological/endocrine/immune research received more than 50% of the total. But I’ve made this point before: if I’m a researcher and I see 20% of such a small amount of money going to psychological research, will I invest the time and effort to submit a biomarker proposal?

Another interesting point is that four of the grants funded in 2012 were new awards (totaling $1,026,377 or 22.7% of the total), and all four of those grants were reviewed by the CFS Special Emphasis Panel. Dr. Susan Maier, chair of the Trans-NIH ME/CFS Working Group, said at the October 2012 CFS Advisory Committee meeting that 18% of ME/CFS applications were funded in 2012, and that this represented a higher success rate than average at NIH. But according to Dr. Sally Rockey, Deputy Director for Extramural Research, that is not the case. Dr. Rockey’s analysis shows that the overall success rate for research grants at NIH in 2012 was 18%. I guess we should be glad for the parity, but if 18% of grants were successful then this means that there may have been only 20 applications for ME/CFS research at NIH in 2012. I checked with several sources, and they estimated that 20 to 22 applications were submitted to NIH last year. Obviously, such a low number of proposals will not get the job done.

XMRV Effect

Another issue that I’ve investigated is the effect of XMRV funding on overall ME/CFS research expenditures. Was XMRV funding raising the overall level of research funding? Or was non-XMRV funding increasing as well? Last year I said: “Spending for 2012 is projected to be $6 million. If all of that money is actually spent on CFS studies, it will represent a significant increase over 2011 because the Lipkin study funding would be shifted to other CFS studies. That would be a significant win for CFS patients.” Unfortunately, the exact opposite happened. When you strip out the non-ME/CFS related grants (including XMRV) for funding in 2008 through 2012, you see this:

	Adjusted Spending	$ Increased (Decreased)	% Increased (Decreased)
2008	$3,175,262
2009	$3,810,851	$635,589	20%
2010	$4,248,535	$437,684	11.5%
2011	$5,009,672	$761,137	18%
2012	$3,696,068	($1,313,604)	(26.2%)

XMRV spending did inflate the spending numbers in 2009-2011, but after stripping that out we still saw an increase in funding during those years. Now we are sliding backward, and fast.

DO SOMETHING

Whether you use NIH’s raw number of $4,518,182 or my adjusted number of $3,696,068, the precipitously decline in funding remains evident. The NIH number represents a 28.8% decrease from 2011, and my adjusted number represents a 26.2% decrease from 2011. This is insane. NIH must do something to stimulate research in this area. There can be no argument about this. NIH must DO SOMETHING!

In testimony at a Senate hearing, NIH’s Principal Deputy Director Dr. Lawrence Tabak stated that NIH spent $386 million in pain research in 2011. NIH now reports that $479 million was spent on pain research in 2012, an increase of $93 million or 24%. One contributing factor for this meteoric increase was that the Affordable Care Act of 2010 included specific requirements for pain research and care. But whatever the reasons, it’s still a boatload of money. To me this reinforces the point that advocates have made over and over and over: there IS money available. It’s just being allocated to “higher priorities” than ME/CFS.

 

For years, the Pacific Fatigue Lab at the University of the Pacific has done the best research on exercise and ME/CFS. Staci Stevens, Dr. Chris Snell, and their collaborators perfected the use of two-day cardio-pulmonary exercise testing (CPET) in people with ME/CFS. Last week, Dr. Snell announced at the FDA meeting that the University had closed the Lab but that the work will continue at new locations.

Snell and colleagues have done more research documenting abnormal CPET results in ME/CFS than anyone else in the field. Beyond documenting abnormal results, the group has also proposed physical therapy regimens based on the metabolic dysfunction revealed in the tests. The Pacific group understands ME/CFS. They do not believe we can exercise our way out of the disease, but they do recommend staying as active as possible within limitations. Stevens was the first to recommend using a heart rate monitor for pacing, and her method is still one of the best out there. When I sought my own exercise testing, I relied on the protocol devised by this group.

So why would the Lab close when it has been such a successful pioneer in this area? Dr. Snell did not elaborate at the FDA meeting, but Stevens says the answer lies in patient services. The Lab has provided exercise testing and disability evaluation to ME/CFS patients for years. I personally know several people who succeeded in disability claims because of the assessments they received in the Lab. Stevens told me that University constraints would no longer allow the Lab to provide this essential service to patients. In order to continue the disability evaluation practice, the Lab had to leave the University.

Stevens created the Workwell Foundation fifteen years ago, and it was structurally meshed with the Fatigue Lab at the University. When the decision was made to close the Lab, Workwell became the backbone of the new effort. Disability evaluation and exercise testing will now be performed in two locations: the XCEL Physical Therapy Clinic in Ripon, California and Sierra Internal Medicine in Incline Village, Nevada (Dr. Dan Peterson’s clinic). Stevens says that the relocation actually enhances the quality of care that Workwell can provide patients. Working in Dr. Peterson’s office will not only offer patients access to his expertise in ME/CFS, but patients can receive IV saline to help them recover from the CPET. That’s an option I wish I had immediate access to last year. At the XCEL clinic, patients will have access to massage therapy to help with recovery, and there is the potential for rehab services in the future. Working with the XCEL Clinic also creates the opportunity for educating rehabilitation professionals, something that Stevens has been doing for years. Stevens says that leaving the University will improve the quality of Workwell’s services because “our new partnerships bring greater diversity, more experience, enhanced services and additional professionals to help with patient care.”

Beyond the disability evaluations, Stevens says that research will continue as well. To me, this is a critical priority. Stevens, Snell and the rest of the team have done excellent work in this area and it needs to continue. Research funding has been and remains a challenge, but Workwell is pursuing grants and other funding in order to continue this research. The research team remains intact. Snell, Dr. Todd Davenport, Dr. Mark Van Ness, and others from the University of the Pacific are staying involved in Workwell. Stevens has also added a Scientific Advisory Committee to Workwell’s structure. Separating from the University may create new challenges for Workwell in terms of grant and research administration, but Stevens says that the team is committed to continuing research in this important area. Several manuscripts are in progress, and members of the team continue to speak at conferences and meetings, including Snell’s presentation at the FDA last week.

Workwell’s goal is “to facilitate an understanding of the biological basis for fatigue and provide objectively determined therapeutic interventions that will improve quality of life” for people with ME/CFS. Fee-for-service exercise testing will provide the basis for disability evaluations, and will help fund more research. Workwell will also continue to educate researchers, health care providers, and policy makers about evaluating and treating people with ME/CFS. Stevens told me that, “We have the same personnel with the same services at nicer facilities.” This change is a new chapter for Stevens and her team, and new challenges will certainly arise, but the core team remains committed to helping people with ME/CFS.

 

See Part One – Tangled Web
See Part Two – CFSAC Specific Recommendations
See Part Three – Care and Services Recommendations
See Part Four – Education and Training Recommendations

Appropriately enough, the CSFAC has made more recommendations on research than any other topic. See pages 1 – 7 of the Recommendations Chart (pdf link). It’s too cumbersome to review them one by one, but we can start by setting aside many as complete or obsolete and then cover the rest by category.

Finished or Obsolete

The greatest number of completed recommendations relate to CDC. Through 2009, the CSFAC made twenty-one recommendations related to CDC research, leadership and funding. Eighteen of those are marked as complete. I think this designation is accurate for several reasons, and in fact, I consider all twenty-one to be complete or obsolete. For example, I think recommendations related to the restructuring of the CDC program in November 2007 should be discarded as either extremely unlikely (e.g. place an extramural effort in the Office of the Director) or irrelevant (e.g. recommendations from the Blue Ribbon Panel). All of the recommendations related to the composition and focus of the Blue Ribbon Panel from May and October 2008 are also obsolete, as that Panel met in late 2008. Finally, all the recommendations regarding the CDC’s five year plan are obsolete as that plan has been mothballed ahead of schedule (although I would love to hear the early death of that plan explored at a CFSAC meeting).

Oddly, one of these completed recommendations was included in the CFSAC’s High Priority list. One of the five-year plan recommendations included a subpart saying that “Identification of biomarkers and etiology of CFS” should be a priority area (May 2009). I’ve previously explained how that subpart was combined with other recommendations to create a new recommendation never voted on by the Committee.

There are several other recommendations that I think should be discarded as obsolete. The recommendation for a intramural staffed laboratory (September 2004, repeated August 2005) and the recommendation for CDC and NIH to sponsor focused workshops (September 2004, repeated August 2005, marked complete by CFSAC) have been partially acted upon, and the language probably needs clarification to reflect that. Both the recommendation to include CFS in the NIH Roadmap Initiative (November 2006) and endorsement of the NIH State of the Knowledge meeting (October 2008) are accurately marked complete. Another recommendation is omitted from the Recommendations Chart, but might be considered complete in any case. The September 2004 recommendation urges the use of a Request for Applications with set aside funds. NIH did in fact issue an RFA for CFS in 2005, so it’s fair to mark this one complete.

Two recommendations marked complete on the Recommendations Chart are not complete, in my opinion, and I cover those below. In addition, one recommendation was omitted from the Chart, and one was miscategorized as Research and I covered it in the Education section. By my count, that leaves fifteen recommendations for review. These break down into recommendations on Centers of Excellence, NIH funding, and specific kinds of research.

Centers of Excellence

The CFSAC has long supported the idea of regional centers for CFS that would offer the best care, as well as opportunities for research and education. The specifics have changed over the years as the Committee has repeated and refined the idea, but they have recommended such Centers six different times. Three of them have no progress reported:

Direct the NIH to establish five Centers of Excellence within the United States that would effectively utilize state of the art knowledge concerning the diagnosis, clinical management, treatment, and clinical research of persons with CFS with funding in the range of $1.5 million per year for five years. (9/04; 8/05)

Establish Regional Centers funded by DHHS for clinical care, research, and education on CFS to provide care to this critically underserved population, educate providers, outreach to the community, and provide effective basic science, translational, and clinical research on CFS. (5/09)

Establish Regional Centers funded by DHHS for clinical care, research, and education on CFS. (10/09)

Two recommendations are presented on the Chart in abbreviated form. The May 2007 recommendation includes five paragraphs of text laying out the dire need for research and clinical care and how regional centers could begin to meet that need. The Chart includes only the bolded text from that page:

HHS establish 5 regional clinical care, research, and education centers, centers which will provide care to this critically underserved population, educate providers, outreach to the community, and provide effective basic science, translational, and clinical research on CFS. (5/07)

The October 2010 recommendation is an odder situation. Both the Chart and the CFSAC webpage for the recommendation list only two sentences:

Develop a national research and clinical network for ME/CFS (myalgic encephalomyelitis/CFS) using regional hubs to link multidisciplinary resources in expert patient care, disability assessment, educational initiatives, research and clinical trials. The network would be a resource for experts for health care policy related to ME/CFS. (10/10)

However, the minutes of the meeting indicate that the recommendation continued for several paragraphs more. The text makes the argument for why centers would address physician education, clinical care and translational research, and further recommends a national network of large databases to support sub-typing and focused treatments. (CFSAC Minutes, October 14, 2010, pp. 53-56)

The most recent recommendation in this category is from November 2011:

CFSAC would like to encourage and support the creation of the DHHS Interagency Working Group on Chronic Fatigue Syndrome and ask this group to work together to pool resources that would put into place the “Centers of Excellence” concept that has been recommended repeatedly by this advisory committee. Specifically, CFSAC encourages utilizing HHS agency programs and demonstration projects, available through the various agencies, to develop and coordinate an effort supporting innovative platforms that facilitate evaluation and treatment, research, and public and provider education. These could take the form of appropriately staffed physical locations, or be virtual networks comprising groups of qualified individuals who interact through a variety of electronic media. Outreach and availability to underserved populations, including people who do not have access to expert care, should be a priority in this effort. (11/11)

This recommendation was included in the High Priority list. It was also addressed in Assistant Secretary Dr. Howard Koh’s response to the Committee on August 3, 2012 (pdf link). Dr. Koh said that the Ad Hoc Workgroup was developing a Department-wide plan and opportunities for interagency collaboration. CFSAC recommendations would be considered by the Workgroup, and the finished plan would be posted on the CFSAC website. But readers of this blog will remember that in reality, we will not be getting a plan and the chances of funding regional centers seem very slim indeed.

 NIH Funding

If CDC-related recommendations have been accurately marked complete, the same is not true of the NIH-related recommendations. NIH is the largest source of biomedical research funding in the Unites States, and it is appropriate for it to be the focus of the CFSAC.

Only one recommendation is not expressly about the amount of funding available from NIH. At the October 2012 meeting, the Committee recommended “establishing a dedicated standing committee for ME/CFS at NIH.” The Recommendations Chart contains a note referring to the Trans-NIH ME/CFS Research Working Group, although the document referenced is not responsive to this recommendation. But the minutes of the meeting make clear that what was contemplated by the CFSAC was not a standing committee like the Trans-NIH group already in existence, but a standing study section responsible for reviewing ME/CFS related grant proposals (CFSAC Minutes, October 3, 2012, p. 44).

The same cannot be said for the other CFSAC recommendations on NIH funding:

Based on the positive response to the NIH’s Request for Applications issued in July 2005 (funded in 2006), the Committee recommends equivalent funding for a second RFA. (11/06)

CFSAC recommends to the Secretary that the NIH or other appropriate agency issue a Request for Applications (RFA) for clinical trials research on chronic fatigue syndrome/myalgic encephalomyelitis. (11/11)

Both of these recommendations are marked as complete on the Chart. The notes refer to NIH Program Announcements which do not have dedicated funds set aside. As I have said to the CFSAC in the past, a recommendation for an RFA with set aside funds cannot be considered completed through program announcements with no dedicated funding.

The last two recommendations have no progress noted on the Chart.

ME/CFS is an illness with enormous economic and human costs. The April 2011 NIH State of Knowledge Workshop identified a number of gaps in what is known about the illness. To address these gaps warrants an interagency effort comprising, but not limited to, NIH,CDC, and AHRQ. Further, the focus should be on interdisciplinary discovery and translational research involving interacting networks of clinical and basic science researchers. Areas to be examined would include the following: identification of patient subsets for detailed phenotyping and targeted therapeutic interventions, biomarker discovery, systems biology approaches and disability assessment.(5/11)

CFSAC recommends that you instruct the NIH to issue an RFA (funded at the $7-10 million range) for projects to establish outcomes measures for ME/CFS diagnosis, prognosis and treatment which would include but not be limited to biomarker discovery and validation in patients with ME/CFS. (10/12)

The May 2011 recommendation is notable for its inclusion on the High Priority list. However, as I’ve previously noted, the recommendation was substantially altered both on the Chart and on the list. Specifically, both documents delete the following text:

To facilitate the above goal, CFSAC recommends that ME/CFS research receive funding commensurate with the magnitude of the problem and that the NIH (and/or other appropriate agencies) issue an RFA specifically for ME/CFS.

If this recommendation is to be designated as a high priority, the full text must be included. That deleted sentence sets the spending level (commensurate with the problem) and the method (an RFA). These are essential elements of the recommendation.

Specific Types

Finally, CFSAC has made recommendations that focus on particular topics or kinds of research. I’ve listed each in its entirety below along with any relevant notes from the Chart.

DHHS should provide funds to develop an international Network of Collaborators that would allow for multidisciplinary CFS-related research using standardized criteria accepted by the international CFS research community. (9/04, 8/05)

The full recommendation continues, “Such a network would pool large number of patients from around the world, and would require investigators to develop and employ common protocols.” This is different from the Centers of Excellence recommendations because it specifically contemplates international collaborations and standardized criteria and common protocols.

Promote, encourage, and fund research directed toward the diagnosis, epidemiology, and treatment of CFS in children and adolescents. (9/04; 8/05)

This recommendation is marked completed and the Chart refers to several program announcements in the notes. However, this focus area is one of ongoing concern and it does not seem fair to consider it finished.

Finally, two recommendations from October 2012 focus on specific patient populations. The Chart assigns the agency responsibility to CDC, but it seems to me these are relevant to NIH as well:

CFSAC recommends that you allocate specific funds to study patients with ME/CFS from past cluster outbreaks. (10/12)

CFSAC recommends that you allocate funds to study the epidemiology of patients with severe ME/CFS. (10/12)

 Keep in Mind

Of the fifteen recommendations, six relate to the Centers of Excellence concept. Four recommendations relate to NIH RFAs, and one was intended to create a permanent committee (or study section) and NIH. The last four recommendations relate to international collaboration, pediatrics, cluster outbreaks, and severely ill patients. More than any other category, the recommendations on research have been condensed in the Chart and much of the excluded language is important. This has to be considered when selecting recommendations for the final designation as high priority.

The news didn’t make much of a splash, but NIH recently issued a funding opportunity announcement that could benefit people with CFS. This purpose of this funding opportunity is to support “collaborative translational research projects” aimed at turning basic discoveries into “clinical applications that improve health.”

Unlike other NIH program announcements for ME/CFS, this one is focused on collaborations between NIH investigators at the NIH Clinical Center and researchers at labs outside NIH. The NIH Clinical Center has pioneered many treatments, including the first trial of AZT in AIDS patients and many new chemotherapy treatments. Dr. Harvey Alter, known to many CFS patients because of his involvement in the XMRV saga, is Associate Director of Research in the Department of Transfusion Medicine at the Clinical Center and a member of the Trans-NIH ME/CFS Working Group.

The NIH Clinical Center has an extraordinary set of resources for translational research, including banked specimens, high grade equipment, healthy volunteers, and experience in clinical trials. How could this be relevant for ME/CFS? Imagine bringing patients into the clinic for a pathogen study or complete neurological workups. Imagine accessing the best equipment and researchers to analyze spinal fluid from patients and controls. Most projects into the causes, diagnosis, and treatment of CFS could be done in partnership with the Clinical Center.

Fourteen institutes at NIH joined together on this program announcement, including the Office of Research on Women’s Health which chose to highlight ME/CFS as an area of interest for this funding:

One of the goals of the WG is to increase focus on collaborative ME/CFS research by identifying NIH resources that may be useful to advance the translational research within this field. ORWH encourages applications from investigators to address research questions focused on the etiology, diagnosis, underlying mechanism, or treatment of ME/CFS.

Note that this announcement is not an RFA with dedicated money set aside, and many areas of interest are highlighted. However, this represents an extraordinary opportunity for CFS researchers. NIH is offering a pre-application webinar on January 11th for interested applicants. I hope we will see applications from institutions and researchers in the CFS world to collaborate with the Clinical Center.

 

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.

 

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.

I delivered the following testimony via telephone to the CFS Advisory Committee on October 3, 2012.

I would like to note something that Dr. Nancy Lee said today: “Nothing about me without me.” That’s what we’re asking for. FDA is moving in this way. We want HHS and its agencies to do so as well. Do nothing about me without me. Take our input. Leverage our expertise. We are highly motivated to assist you.

Even the newest members of this Committee have heard enough testimony from patients to recognize the despair that comes from living with a disabling, incurable disease that is barely recognized by most healthcare providers. My fellow advocates have spoken eloquently about the grinding isolation, pain and despair that they endure day after day.

But no one talks about the despair engendered by these meetings and the work of this Committee. I have heard many patients say that they don’t believe this Committee will ever help them. That there is no point in following your work because the government does not listen to your recommendations. There are patients who have abandoned the hope that this Committee will produce meaningful change. Their lives are the same, day after day, and they believe that all this Committee does is talk. After each meeting, and even today, I’ve observed a surge in frustration, disappointment and despair among my fellow advocates because another opportunity for progress has been lost.

Everyone at the table today has invested many hours in the work of this Committee. Regardless of your good intentions and engagement in these discussions, what matters to patients is meaningful change. If good intentions were all that was needed, we would have been cured long ago. Patients are looking for concrete progress, and they don’t see it here.

What do I mean by concrete progress? Performance measurement and metrics are buzzwords, but it all comes down to measuring change. Dr. Maier’s slide on the approval rates for ME/CFS proposals to NIH is an excellent example of this. Another hypothetical example is that NIH says that there are not enough ME/CFS research applications coming in to justify an RFA. But what if we could measure progress on that? First, we would need to know how many applications would be enough; that would be the goal. Then at each meeting, NIH could report on how many applications had been received in the previous six months. We could see whether the number of applications was increasing or decreasing over time, and we would know exactly how far we were from reaching the goal. This type of goal setting and progress measurement could be repeated across all the domains of this Committee. In my experience, knowing where you stand relative to a goal naturally leads to more targeted action.

But we don’t measure progress that way right now. The only goals we have are your recommendations, and the only measurements we see are the responses noted in the Recommendations Chart, which has not been updated since November of last year. And this is why we despair after each meeting – nothing is changing in our lives and we can’t identify what progress is being made, if any, through this Committee.

In the absence of metrics from your side of the table, I thought I would share with you my own metrics. I tracked a variety of things in my day-to-day life in order to share some concrete numbers with you.

• 111 days have passed since your last meeting
• I have been disabled for all of those days
• I left the house a total of 21 times, typically for three hours or less
• 5 of those outings were for healthcare visits
• I had an additional 9 email and phone exchanges with my healthcare team
• I paid to have groceries delivered 7 times
• I paid to have my house cleaned 7 times
• My doctors currently prescribe 9 different medications for me
• I took a total of 1,554 pills since your last meeting
• I had 4 episodes of tachycardia and near fainting
• There were 14 days since your last meeting when I could not get out of bed
• I could not drive a car at all
• I could not take a walk at all
• This Saturday is the 18^th anniversary of the day I got sick. If I had given birth on October 6, 1994, that child would now be an adult.
• ME/CFS ripped into my life 6,567 days ago. I could have spent those days building my legal career or writing books, or maybe both.
• Instead, for 6,567 days I have endured every insult and change that ME/CFS has thrown at me.

These are my metrics and this is my charge to you: Show me progress. Show me measurable change. Make a difference so that I can stop counting how many days and how many ways ME/CFS is destroying my life.

UPDATE: You can watch the meeting via webcast OR you can call in to the meeting in listen-only mode at  1-866-761-7202. Passcode: 3117619.

 

The CFS Advisory Committee will meet on Wednesday and Thursday this week. The registration deadline for attendance and for public comment has passed, but I’ve collected some important links for you. I will be watching the meeting (and I hope you will too!) and will publish a summary on Friday.

• The Federal Register notice for the meeting indicated:  “The meeting will be live-video streamed at www.HHS.gov/Live  . . . Listening-only audio via telephone will be available on both days. Call-in information will be posted on the CFSAC Web site.” The video link is not working, Update: the link is now working but still no call-in information has been posted yet.
• The agenda for the meeting was posted after the deadline for comment registration had passed.
• Public comment is scheduled for both days of the meeting, and will include comments from Lori Chapo-Kroger, Mary Dimmock, Pat Fero, Sue Jackson, Matthew Lazell-Fairman, Alexander Lopez-Majano, Denise Lopez-Majano, Jadwiga Lopez-Majano, Matthew Lopez-Majano, Billie Moore, Faith Newton, Matina Nicholson, Donna Pearson, Amy Squires, Charlotte von Salis, and me.
• For background on how the committee functions, check out my post CFSAC Basic Facts.
• Hopefully we will hear an update on the Department of Health and Human Services Ad Hoc Working Group.
• I am continuing to investigate the committee’s membership background, including who nominated them and profiles of new members Dr. Adrian Casillas and Dr. Lisa Corbin.
• One member of the committee resigned shortly after the meeting in June 2012. The committee bylaws (not currently available on the website) require a replacement be appointed within 90 days but there is no indication on the agenda that a new member will be sworn in for this meeting.

You may recall from my post on the Lipkin study that Dr. Lipkin talked about the sample cohort at the press conference on September 18th. Dr. Lipkin said that the samples would be available for other investigators and that applications to use the samples should be made through NIH. In his interview with Dr. Vincent Racaniello on This Week in Virology, Dr. Lipkin said:

We’ve been able to store sera and PBMC so that other investigators who want to do either microbiology, or genetics or proteomics will be able to access those samples through the NIH. There will be calls for proposals, and there will actually be funding associated with that.

During the interim, we offered the laboratories and the investigators and the clinical sites who were engaged with this work to put forward proposals to do something with these materials in advance of that RFA, though without any funding. Two of those groups..well, several groups applied. Two of them were selected by the entire team, and they will be receiving plasma samples that they can then study. The primary focus has been on microbiology and genetics, but I’m sure there will be other applications as well. (emphasis added)

Obviously, the availability of these samples and the possibility of funding is of great interest to the CFS community. NIH spent more money on the Lipkin study than any other CFS study in 2011, and the results came well after the XMRV question seemed settled with the retraction of the original study by Science. If the samples can be used in future studies, especially if NIH provides funding for such studies, then that will be a huge win for CFS.

I asked Dr. Susan Maier, chair of the Trans-NIH ME/CFS Working Group and ex officio representative to the CFS Advisory Committee, for additional information. She provided the following clarifications by email on September 21st:

We are very pleased that Dr. Lipkin has offered to make remaining specimens available to any ME/CFS investigator who successfully competes for NIH funding.   Dr. Lipkin and NIH program staff agreed that the NIH peer review process would offer the fairest means to decide who should have access to these samples.  Consequently, interested investigators will be advised to consider currently available and relevant NIH funding opportunities in order to pursue these samples. NIH will be issuing a notice in the NIH Guide to Grants and Contracts very soon that will elaborate upon these points.  However, it is important to note that there are no set-aside funds associated with these samples.  In addition, Dr. Lipkin’s laboratory will maintain these samples, which is standard NIH protocol. They will not be stored at NIH.

With regard to the two investigators who have already received samples, Dr. Lipkin was referring to his study collaborators.  This is separate from the process described above. (emphasis added)

So there will NOT be any set aside funding or RFA. Investigators will apply through NIH and the normal NIH peer review process, but there will be no new money. I’m not sure why conflicting statements were made by Dr. Lipkin and Dr. Maier. The last RFA from NIH for CFS research was in 2005, and the CFS Advisory Committee has recommended that NIH issue RFAs many times over the last decade. I had hoped that Dr. Lipkin was correct and that we were on the verge of securing an RFA. It appears we will continue to wait.

 

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.