Reading Tea Leaves

Posted on March 24, 2014 by Jennie Spotila
Credit: Veterans News Now

Credit: Veterans News Now

In a report issued on March 12, the IOM panel tasked with creating a new case definition for Gulf War Illness declined to do so. This is the first time the IOM was attempting to create a disease case definition, and many ME/CFS advocates (myself included) awaited the report with much trepidation because of the clues it might hold for how the ME/CFS case definition effort would turn out. It didn’t take long for ME/CFS advocates to weigh in (see posts by Jeannette Burmeister, the CFIDS Association, and Cort Johnson). I take no comfort in this report, but I also don’t believe we are automatically doomed.

What the GWI Panel Did

The panel was tasked with reviewing the published literature and holding discussions with researchers and clinicians in order to create a new case definition for GWI (referred to as chronic multisymptom illness in the report and by the Veterans Administration) and to make a recommendation regarding the illness name. They reviewed the case definition and population studies conducted on Gulf War veterans, the largest of which included more than 19,000 subjects. They considered the published data on the symptoms and exposures reported by both deployed and non-deployed Gulf War era veterans, looking for data to support the key elements of a case definition. And they came to a startling conclusion.

The panel said they could not create a new case definition. Why? Because there isn’t enough data, or at least not enough of the right kind of data. The key paragraph is on page 96:

After a thorough discussion of that literature, the committee concluded that it was not feasible to develop a new evidence-based definition of CMI. The case-definition studies do not all consistently identify period of onset, duration, frequency, severity, exposure, exclusionary criteria, or a uniform set of symptoms. There are no clinically validated tests or measures for diagnosing CMI. Furthermore, the symptoms of CMI are not unique to Gulf War-deployed veterans although they occur in the deployed at a higher frequency and with greater severity than in nondeployed era veterans or those deployed elsewhere. . . . Thus, the committee has concluded that the available evidence is insufficient to develop a new case definition of CMI inasmuch as the data are lacking for key elements of a case definition of a symptom-defined condition, which might include, for example, onset, duration, and measures of severity.

The panel went on to identify two case definitions (CDC and Kansas) that captured the common set of symptoms identified in all the case definition studies. The CDC definition is broader because it requires fewer symptoms than the Kansas definition, and does not identify exclusionary conditions. However, the panel said that “neither definition has been sufficiently validated.” The panel recommended that the VA systematically assess the data to see if it could identify some of those missing case definition elements, and that the term CMI be replaced by “Gulf War illness.”

Speaking of ME/CFS

Perhaps it’s not surprising, given the presence of both Dr. Fred Friedberg and Dr. Suzanne Vernon on the panel, that ME/CFS is briefly discussed in the report (see pp. 26-27). The committee notes that multiple ME/CFS case definitions are in use, although without acknowledging the debate over whether it is one illness or many. After pointing out that ME/CFS diagnosis is based on patient-reported symptoms (like CMI), the committee says that the either-or debate over whether ME/CFS is a physical or mental health disorder is not useful. The report states, “The distinction between mental and physical disorders is often arbitrary, and most patients’ experiences of any illness are influenced by biologic, psychologic, and social factors.”

This is not exactly an unequivocal rejection of the psychogenic theory of GWI or ME/CFS. Personally, I am disturbed by what appears to be a change in tactics for the psychosocial school. This topic needs separate discussion, so I’ve addressed it in more detail in my post Changing Tactics.

Prognosticating

So what does this GWI report tell us about what to expect from the ME/CFS IOM study? The short answer is “not much,” but I see some cause for concern.

What bothers me about this report is that the panel felt the evidence base was insufficient to create a new case definition, and it makes me wonder about our own evidence base. It is true that GWI appear to have arisen at a specific point in time (Gulf War deployment), while ME/CFS is constantly occurring. But there are similarities between the two evidence bases, too.

First, the panel noted an important limitation of the GWI cohort studies: most of them relied on self-reporting of symptoms on questionnaires (p. 34). This potentially introduces reporting bias and recall bias. Many of the ME/CFS case definition studies rely on self-report through questionnaires, too. Our studies are much much smaller than Gulf War studies, too, weakening the evidence base even further.

Second, the panel concluded that the statistical studies reviewed in Chapter 4 (pp. 67-86) “failed to identify a cluster of people that presented with a unique syndrome.” Instead, the studies found that Gulf War veterans had more symptoms with greater severity than veterans who were not deployed to the Gulf, but that the nondeployed still reported similar symptoms. It seems to me that we may be at risk for a similar conclusion, since at least some studies have found high rates of occurrence of ME/CFS symptoms in control subjects.

Third, I was struck by the similarity between some CMI/GWI case definitions and the core symptoms of ME/CFS. For example, the CDC definition (co-authored by Fukuda in 1998, oddly enough) requires one or more symptoms from at least two of three categories: fatigue, mood/cognition, and musculoskeletal. Does this sound familiar to anyone?! There is no onset requirement, meaning that those symptoms could occur at any time in order to qualify. It seems to me that many, if not all, ME/CFS patients would meet this definition too.

Fourth, post-exertional malaise might occur in GWI. Appendix B of the report presents a combined summary of symptoms reported by veterans in the studies discussed in Chapter 3. Fatigue was reported by a median of more than 30% by Gulf War veterans. The fatigue category includes reports of “fatigue lasting 24h after exertion . . . problems with fatigue lasting more than 24 hours after having made a physical effort” (p. 116). Depending on how one defines and measures post-exertional malaise, these results could be interpreted to fit that term. ME/CFS patients experience more than fatigue after exertion; we suffer from an exacerbation of all symptoms (including immune symptoms), and “fatigue” is a completely inadequate word to describe the prostration and collapse. But will the IOM panel realize that? I think many researchers, even those working in the field, may perceive that PEM is a fatigue experience. If PEM is equated to fatigue lasting more than 24 hours after exertion – which is reported by Gulf War veterans – the argument that post-exertional malaise is unique to ME/CFS falls apart.

Finally, the report notes the elements of a symptom-based case definition, including “period of onset, duration, frequency, severity, exposure, exclusionary criteria, or a uniform set of symptoms.” Because these elements were not consistently identified (or identified at all) in the Gulf War studies, the panel could not create a new case definition. The same inconsistency appears in ME/CFS literature. Differences in onset, duration, frequency/severity, exclusionary criteria and core symptoms are found among the case definition and population studies for ME/CFS – especially if you begin by lumping CFS, ME and ME/CFS studies together.

Will They?

Some advocates are optimistic about the ME/CFS IOM panel, citing differences in the committee charge, panel composition, and inclusion of unpublished data. But I think I’ve shown that some of the deficiencies in the GWI evidence base could be applied to the ME/CFS evidence base as well.

For me, it comes down to the panel. The ME/CFS IOM panel could decide that the weaknesses in the evidence base are not as problematic, and create a definition based on what we know. We have the benefit of eight panelists who are personally and/or professional acquainted with ME/CFS, a significant improvement over the lack of GWI experts on the other panel. We simply do not know how they will view the evidence, and how effectively they will advocate with the non-ME/CFS experts.

As much as I would like to share in the optimistic confidence of some ME/CFS advocates, I don’t draw solace from the GWI report. But I also can’t conclude that we’re completely screwed. We have a different panel with a different charge. Ultimately, drawing conclusions from the GWI report is an exercise in reading tea leaves – a rather poor way of predicting the future.

 

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Changing Tactics

Posted on March 24, 2014 by Jennie Spotila

bigstock-Bear-Trap-38159869-e1370296224125For decades, ME/CFS research and clinical care has been plagued by disagreement over the basic classification of the illness. Is ME/CFS a physical disease, as many patients and researchers insist? Or is it a mental health disorder perpetuated by deconditioning, as argued by the psychosocial school? There is growing rejection of the psychogenic explanation for ME/CFS, but it is not disappearing. In my view, the psychosocial school is simply changing tactics, and this is a trap that we must avoid at all costs.

Transforming the Argument

The hypothesis that ME/CFS is a mental health issue has been disproved by the data. For years, the psychosocial school has claimed that CFS patients had poor coping skills and were simply deconditioned. All we needed to do was increase our physical activity (GET) and ferret out our dysfunctional illness beliefs (CBT), and we would recover. While the PACE trial and other research has been based on this premise, we have ample data that cuts the theory off at the knees. The two-day CPET (cardiopulmonary exercise testing) results cannot be faked, and distinguish ME/CFS patients from sedentary controls. Gene expression studies have also shown a distinct pattern of response to exercise in ME/CFS patients compared with sedentary controls and patients with other illnesses. Evidence, including imaging, spinal fluid, and immunological testing, has mounted to the point where Dr. Anthony Komaroff declared that the debate over back in 2006.

But the psychosocial school has not relented and I now see a change in their tactics. Instead of insisting that the illness is psychological, they are waving their hands and saying that the psychological v. physical debate is irrelevant. I offer two recent examples:

First, there is the systematic review of ME/CFS case definitions by Brurberg, et al., which I reviewed in detail in my post Systematic Overreaching. The authors stated:

It is likely that all CFS/ME case definitions capture conditions with different or multifactorial pathogenesis and varying prognosis. The futile dichotomy of ‘organic’ versus ‘psychic’ disorder should be abandoned. Most medical disorders have a complex aetiology. Psychological treatments are often helpful also for clear-cut somatic disorders. Unfortunately, patient groups and researchers with vested interests in the belief that ME is a distinct somatic disease seem unwilling to leave the position that ME is an organic disease only. This position has damaged the research and practice for patients suffering from CFS/ME.

As I said in my comment on the article published on BMJ Open, “The authors presented no evidence to support their accusation that the organic disease -only position has damaged research and clinical practice. Furthermore, they completely ignored the very real and logical possibility that the reverse is true. In other words, it is equally possible that the people with vested interests in the belief that ME/CFS has psychosocial causes are unwilling to leave that position, and have damaged the research and practice for patients suffering from the disease.”

Second, the recent report on the case definition for Gulf War Illness included the following discussion of the mental v. physical debate:

Like CMI and many other symptom-based illnesses, ME/CFS is not without controversy, particularly regarding whether they are mental disorders or physical health disorders [cite to IACFS/ME Primer]. The committee notes that this either-or approach is not useful, for several reasons. The distinction between mental and physical disorders is often arbitrary, and most patients’ experiences of any illness are influenced by biologic, psychologic, and social factors. Either-or thinking leads too often to a presumption that medically unexplained symptoms must be psychogenic. In addition, psychiatric [sic] symptoms may not be fully evaluated if a patient’s symptoms are psychogenic. Although physical and psychologic stress can exacerbate many chronic conditions – including chronic pain, headache, respiratory, and gastrointestinal symptoms – there is an inherent risk in assuming that medically unexplained symptoms assume a “stress-induced” etiology.

As in Brurberg, et al., there is no rejection of the psychogenic theory of ME/CFS. Instead, we’re told to abandon the debate. It’s not either-or, it’s both. Let’s stop arguing about the evidence, and go with a holistic view (that still includes the psychogenic theory).

It’s A Trap

Do you see what’s happening here? The ME/CFS psychogenic school is wrong – as shown by all the data that indicates biological abnormalities that are not seen in sedentary controls or people with depression or anxiety. But instead of admitting the error, they are simply changing tactics. Now they are saying that it’s psychological AND physical, and the distinction does not matter anyway.

Contrary to this new angle on psychosocial explanations, I believe it matters a great deal whether ME/CFS (or GWI) is a mental or physical disorder. The distinction between mental and physical is not “arbitrary,” but can be drawn based on signs and symptoms. I readily admit that my emotional state and coping skills have had an impact on my experience of this disease, but I completely reject the premise that therefore the distinction between mental and physical does not matter. It does.

People with mental health issues are primarily treated by psychologists, and in ME/CFS that usually means CBT and GET. We know that GET can have serious and long-lasting negative effects on ME/CFS patients. For decades, ME/CFS patients have endured dismissal and worse because of the psychogenic view of the disease. To say the distinction does not matter is foolish, at best. The practice of medicine is structured around that duology. There are medical diseases treated by physicians, and there are psychological diseases diagnosed with the DSM-IV (soon to be DSM-V) by psychologists. In the middle are psychiatric diseases like schizophrenia which are known to be biological, but are treated in the mental health setting because the symptoms of disease are behavioral. Mental health diagnoses are treated differently by health and disability insurance. There is a difference between the physical and psychological attributions of illness: in health care, in benefits, and in social views.

If the mental-physical duology no longer applies, shouldn’t that be true of all diseases? If “patients’ experiences of any illness are influenced by biologic, psychologic, and social factors,” then I suppose we are abandoning the dichotomy in cancer, heart disease, and multiple sclerosis too? I don’t know about anyone else, but I don’t hear anyone suggesting that those diseases are psychogenic in any way. I have family members who have endured MS, cancer and heart disease. Stress can make those diseases harder to manage, and even exacerbate the underlying disease process. But no one would ever say “let’s abandon the either-or thinking and agree it’s biologic and psychologic.” No way. Those diseases are accepted as physical in origin, with implications for behavior and coping. I believe that I deserve the same respect.

Bias and Decision Making

I’ve described the psychosocial school as changing their tactics, but I don’t necessarily believe there is a smoke-filled room where a cabal of psychologists sat down and said, “We’re losing the argument so let’s use these talking points instead.” I think the shift may be the result of cognitive bias and the difficulty humans have with admitting they’re wrong.

If I am a psychologist and I’ve invested 10 or 15 years in the theory that CFS is the result of poor coping skills and deconditioning, it’s going to be hard to change my mind. Despite mounting evidence that my theory is wrong, it will be hard to let it go. An easier step is to say that I’m not completely right but also not completely wrong. It’s not either/or, it’s both.

ME/CFS patients have gone through this process themselves. When the XMRV paper was published in 2009, many patients seized on the results. We had very good reasons to do so, and at first, the science and scientists seemed to support that position. But as contrary data emerged, and hard questions were asked, some scientists and patients found it very difficult to follow that data. They continued to insist that it was XMRV, and when that was disproved they claimed it was HGRVs. And when that was disproved, they claimed the science hadn’t been done right or there was a conspiracy or there were unidentified retroviruses at work. And it was three years before Dr. Mikovits finally took the courageous step of publicly admitting her conclusions had been wrong.

Nobody likes to admit a mistake, and the more you have invested in that mistake the harder it is to admit it. The psychogenic explanation of ME/CFS is wrong, but instead of admitting the mistake, some scientists are shifting gears and saying that it’s not completely wrong because the physical-psychological divide doesn’t actually matter. They are not following the data, and they are attempting to twist the dialogue so they don’t have to admit they are wrong.

Drawing the Line

The divide matters, and I will not be drawn into a compromise view. ME/CFS is a physical disease with physical causes. My emotions are relevant to my ability to cope with this physical disease, just as emotions are relevant to coping with cancer or AIDS. But I reject any hypothesis that leaves the psychogenic view on the table. Not because I don’t want to face up to having a mental illness. Not because I want my disease to be physical. Not because I am personally prejudiced against mental illness and not because I don’t see the relevance of emotions in physical health. I reject the psychogenic hypothesis because the data is not there.

I had a happy childhood. I had a satisfying career and personal life. I enjoyed being physically active. Then I got sick. And despite my strong desire to continue in that career, that personal life, and that physical activity, I have not been able to do so for almost twenty years.

The reasons why my life was destroyed matter. The cause of that destruction matters. To say that the distinction between physical and psychological causes is arbitrary and irrelevant is to dismiss my experiences. It may save face for the psychogenic school, but it is a slap in mine. I challenge the researchers and decision makers to admit their errors, and get on with the business of finding the answers that will repair my body and my life.

This post was translated into Dutch, with my permission.

 

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Infused

Posted on March 19, 2014 by Jennie Spotila

photoI’m beginning a new experiment: IV saline. Regular saline infusions have been used by many ME/CFS patients to cope with orthostatic intolerance for years, but I’ve never taken them regularly. Yesterday, I received the first of four weekly treatments. How much to take, and how often, is trial and error. If it helps me, then perhaps this will be an ongoing treatment (hopefully at home). In the meantime, here’s what I learned in the infusion center yesterday:

  1. No matter how sick and disabled I feel, I am still the healthiest patient in the chemo suite.
  2. Noise cancelling headphones are essential equipment.
  3. Bending my arm the wrong way not only hurts, but it sets off an earsplitting alarm on the infusion pump.
  4. It’s cold. I need a better strategy than covering up with my jacket.
  5. I should not have bothered bringing the IOM Gulf War Illness case definition report. Reading? Ha!
  6. I would be better off saving the weekly episode of This Week in Virology for infusion entertainment.
  7. Be very flexible and very patient. See Lesson #1.
  8. I ended the infusion with the familiar tired but wired feeling. Listen to the “tired,” Jennie, and go to bed when you get home.
  9. I am very blessed to have friends willing to drive me to and from infusion. Not being able to drive myself stinks.
  10. I experienced a weird awareness that I had no appetite but knew that I really needed fuel. Plan ahead and bring a snack.
  11. I struggled with a lot of guilt during the infusion, like I didn’t deserve to be there because I wasn’t receiving chemo.  But my doctor and I believe this is a necessary experiment. I had to remind myself many times that I am just as deserving of healthcare as everyone else getting infusion.
  12. I need to pay careful attention to how I feel, and whether the IV helps. But I also need to be careful about my expectations. This may help; it may not. I’ll try to take it as it comes.

 

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Not So FOIA

Posted on March 17, 2014 by Jennie Spotila
Credit: Maxwell Air Force Base

Credit: Maxwell Air Force Base

The problems ME/CFS advocates are having with Freedom of Information Requests are swiftly acquiring epic proportions. Jeannette Burmeister filed a lawsuit this year to compel release of documents for one of her FOIA requests. Patricia Carter has also filed FOIA requests with several agencies. I’ve got so many open FOIA requests that I have to track them on a spreadsheet, and several have been pending for years. Out of fifteen total requests, I’ve received final responses to only five of them.

Now a new report from the Center for Effective Government says we are not alone.

According to Making the Grade: Access to Information Scorecard 2014, the Department of Health and Human Services received a barely passing grade of 61% or D-. This ranked them right in the middle of the 15 agencies scored in the report. According to the report, HHS responds to 68% of its FOIA requests within 20 days, and fully grants 85% of all requests. This is pretty good, but HHS got a failing grade on its disclosure rules for failing to update its FOIA regulations to comply with the 2007 changes to the statute and for communicating poorly with requesters. I dug into some of the data available for each agency, and found it’s not as simple as the overall grading suggests. For example, the Center for Medicare and Medicaid Services received almost 77% of all FOIA requests to HHS in FY2013, and responded to 86% of them within 20 days. That’s going to skew the numbers for the Department overall.

Since most of my requests are pending with CDC, NIH and the Assistant Secretary’s Office (OASH), I took a look at the numbers to see how my experience compares with those offices’ data overall.

CDC FOIA Requests

In 2013, CDC responded to about a third of its requests, denied another third, and left a remaining third in its backlog. Average response time was far over the required 20 days, ranging from 90-150 days on average depending on the complexity of the request. My oldest pending FOIA request was filed with CDC in July 2012, and I have received no response to it. But I’m not alone. The oldest request pending at CDC was filed in July 2008. Mine is one of 494 backlogged requests as of the end of FY2013.

NIH FOIA Requests

In FY2013, NIH granted 70% of its requests in whole or in part. Average response time was 15 days for simple requests and 70 days for complex requests. The quickest response time I’ve ever experienced for a request was with NIH: eight days from request to response. I’ve experienced longer response times too. One request, that I‘ve blogged about before, took 100 days for the initial response. However, I appealed that response and waited almost a year for a response to the appeal. That’s shorter than the average HHS appeal time of 510 days, but far longer than the 20 days required by FOIA. The response was unacceptable, so I am continuing in this appeal.

OASH FOIA Requests

In FY2013, OASH granted 68% of its requests in whole or in part. For simple requests, OASH responded within an average of 8 days, but complex requests took an average of 220 days. I have multiple requests pending with OASH, the oldest dating from December 2012. I received interim responses on that one in August and September 2013, and have been arguing with OASH over the documents since then.

Lessons and Options

fix-foiaOne of the things I’ve learned from submitting so many FOIAs is to be as specific and detailed as possible, but also as limited as possible. Agencies classify incoming requests as “simple” or “complex,” and the simple ones are filled first. Unfortunately, no definition of “simple” or “complex” is available to help requesters tailor their requests to make it more likely to be categorized as simple. While it feels like an unnecessary waste, I’ve also learned to separate my requests. When I’ve asked for a number of different documents in a single request, the whole thing gets slowed down. Now I file each request individually.

Long response times are certainly not unusual according to the data, but that doesn’t make it right. In fact, delays in releasing documents have a direct impact on advocacy. Jeannette’s lawsuit is for documents related to the IOM panel. Obviously, delays in releasing those kinds of documents helps HHS and impairs advocates’ ability to act on complete information. But lawsuits are expensive, both in time and financial cost. There are additional options, though.

There is a federal FOIA Ombudsman that may help mediate disputes between the requester and the agency. They have a very small staff, but I am receiving their assistance with several of my pending requests. Another option is to work with your Congressman’s office, as sometimes they can provide assistance in drafting requests or applying some pressure.

The Obama administration, which has been criticized for not following through on open government, is considering issuing a single FOIA regulation for all agencies. This could be very helpful, as each agency currently has its own set of regulations, but it will probably take a few years to negotiate and issue a final regulation.

Finally, there is legislation currently pending that would, among other things, require agencies to release documents unless they can show foreseeable harm from the release. This would be fantastic, because what I’m finding in my requests is that information is withheld for no reason other than the agency doesn’t want me to have it. The current FOIA exemptions have been interpreted in such a way that they can do this (or try, anyway). This leads to lengthy appeals, and significant delays in getting documents that should have been released to begin with.

Public Interest

I’m sure there are abuses of FOIA, where someone requests documents for no purpose other than to annoy the agency. That is not the case with ME/CFS advocate requests, however. Jeannette, Patricia, myself and others file FOIA requests for documents we need and are entitled to have. There is a strong public interest in knowing who nominated CFSAC members, and why some of them have resigned. There is a strong public interest in seeing the IOM contract.

None of us are doing this for personal gain. We want to hold our government accountable for its actions, and we need the documents to do that. I will continue to file FOIA requests (and appeal erroneous decisions), and report the results to you. And maybe, dare I hope, the government will change its behavior if it realizes that our FOIA requests will ensure transparency and accountability.

 

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Exit Stage Right

Posted on March 13, 2014 by Jennie Spotila

Another CFS Advisory Committee member has resigned.

After the March 11, 2014 CFSAC meeting, I emailed the Office of Women’s Health and asked for a list of who had attended the meeting. I tried to keep track of the roll call, but there were clearly technical difficulties that prevented several members from answering and it wasn’t clear when they arrived. The CFSAC Support Team responded yesterday:

All of the voting members of the committee participated in the webinar yesterday (n=10), so a quorum was present.  (We have one vacancy – Dr. Dimitricoff [sic] resigned a few weeks ago.)  All voting members were present at the start of the webinar, except one member who was ~ 5-10 min. late. (emphasis added)

I have to wave several red flags here, and I would jump up and down too, if I could:

Red Flag #1: As of this post (March 13th), Dr. Dimitrakoff is still listed on the CFSAC roster.

Red Flag #2: No one mentioned Dr. Dimitrakoff during the March 11th meeting. I thought it was odd that Dr. Marshall didn’t call his name during roll, but assumed that he was simply unable to attend. It is completely inappropriate not to announce to the public that a member has resigned! Do the other CFSAC members even know? When were they told? Why were we not told?!?!?!?

Red Flag #3: This means that SIX members are departing the committee in 2014. That means that a majority of the committee (6 of 11) will be new members this year. In addition, two members were added in 2013 (Ms. Collier in May and Dr. Kaplan in October). And Dr. Nancy Lee currently provides no orientation whatsoever for new members. NONE.

Red Flag #4: Dr. Dimitrakoff was assumed by many advocates to be the heir apparent to replace Dr. Marshall as Chairman. Now it appears that the Chairman will be selected from the five remaining members: Dr. Casillas, Dr. Corbin, Dr. Fletcher, Dr. Kaplan, or Ms. Collier.

The CFSAC is being eviscerated. A majority of the committee will be new this year. Two of the five “veterans” will have served only a year. Of the five “veterans,” only one can be considered an ME/CFS expert, meaning that a significant portion of his/her time is spent on ME/CFS research or clinical care.

I shudder to think what this Committee will look like by the end of 2014 (assuming the charter is renewed in September, of course). Several steps must be taken to mitigate the risks to the ME/CFS community: the six new appointees must be ME/CFS experts and all of them should receive substantial orientation so they can hit the ground running.

 

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Silver Platter of Frustration

Posted on March 12, 2014 by Jennie Spotila

Yesterday’s CFS Advisory Committee meeting was insane. Wait, maybe the meeting just drove me insane. Or was the whole thing just insanely inane? I don’t even know anymore. Wait a second, hang on.

keep-calm-and-bang-your-head-against-the-wall

Ok, let me start again.

Yesterday’s CFS Advisory Committee meeting served up a generous helping of frustration on a silver platter. While some of the mistakes from the last meeting were corrected, many mistakes were repeated and new ones were made. I’m going to be as succinct as possible in summarizing another episode of Tech, Wreck and Waste.

Webinar 101

Let me make this very straightforward and very simple: Do not run a webinar if you cannot make a webinar run. Here’s a checklist:

Can you provide clear audio? Some speakers were unintelligible. Dr. Sue Levine’s audio kept cutting out during her presentation. And for seven minutes (I timed it), the audio cut out completely. The closed captioning was not an adequate substitute, but did provide comic relief with such gems as translating “criteria” as “cry tears.”

Do you know how to use the slides? I really expected this to be nailed down after the fiasco that was the slide portion of the December meeting. But I was wrong. There were nine minutes (I timed it) at the beginning of Dr. Dane Cook’s presentation during which we listened to dead air followed by a discussion of whether members could advance the slides themselves, which buttons to push, which slides they were seeing, and so on. From this point on, the slides periodically caromed out of control, moving backwards and forwards to the point where I got dizzy and had to look away from the screen. Several times, the slides disappeared completely.

Have you secured your dog in another room? I love dogs. I own a big lug of a dog, and I know that you cannot always control what your dogs do or when they will decide to bark their fool heads off. Which is why, if you are speaking on a webinar, you should arrange for your dog to be in another room. It was hard enough to follow the sometimes chaotic discussion without distractions like background noise.

Have you anticipated technical difficulties and rehearsed ways to fix them if they arise? Slide problems. Sound problems. Conferencing people in and out problems. This went a little better than December, but still, it really isn’t rocket science to practice solutions in advance.

If you answered “No” to one or more of these questions, you are not ready to run a webinar.

The tech problems have real consequences for the public trying to follow the meeting. We don’t know who is speaking (or even who is present), the slides do not always advance with the discussion, and sound problems mean we can’t hear some discussion at all. It was very clear that CFSAC members are equally frustrated by these difficulties. In my opinion, the webinar format should be abandoned until these technical issues are solved.

Stupid Questions

I believe there is really only one kind of stupid question: the question you do not ask. And there were some doozies.

  1. Not a single question for FDA about the Draft Guidance to Industry document. If I could read it and come up with a list of questions, why didn’t CFSAC members?
  2. Not a single question for AHRQ about the systematic evidence review. The evidence review is not only the cornerstone of the P2P Meeting, it is arguably just as significant (and long-term in its implications) as the IOM study. I have a looong list of questions about it. But maybe that’s just me.
  3. Little discussion about Dr. Cook’s presentation from the research and clinician-scientist recruitment working group. It seems like a lot of work went into that, and there were many potential topics for discussion. But from my notes, it looks like 15 to 20 minutes of discussion occurred.
  4. Not a single question for CDC, despite an issue that demanded strong questioning. (see the next section)
  5. Not a single question about the CFSAC charter renewal process.
  6. Not a single question about the appointment of a new Chairman.
  7. Not a single question about the timeline for appointing new members.
  8. Not a single question about what HHS is doing to ensure the coordination of the multisite study, P2P process, and IOM study – or even why these are all being pursued simultaneously to begin with.
  9. Not a single questions about the status of the High Priority Recommendations, and whether any have been completed.
  10. Not a single question about the status of adding links to ME/CFS organizations on the Office of Women’s Health website.

I Call Shenanigans

keep-calm-and-call-shenanigansDr. Sue Levine and the medical education working group were justifiably critical of CDC’s CFS website. Dr. Levine even suggested that someone investigate the potential for legal action against CDC to force some movement on the changes CFSAC has repeatedly recommended. At a minimum, she advocated that CFSAC identify who is responsible for the website in order to identify and deal with the roadblocks.

Dr. Belay (who had not responded during any of the roll calls so I’m not sure when he joined the meeting) jumped in to say that CDC has extensively revised the website based on committee input. The TookKit has also been revised, although he admitted that CDC had not taken down the old version as recommended by CFSAC. Dr. Levine asked what was causing the delay in making changes, and Dr. Belay responded that “we’ve made the changes a few months to a year ago.”

This is not true, as any CFSAC member could have established very quickly.

Denise Lopez-Majano checked the CDC website, as each page identifies when the content was last reviewed. The homepage? May 2012. General information page? May 2012. CDC CFS Publications? April 2012. Continuing education? July 2012. Case definition? May 2012. Symptoms and Causes and Diagnosis and Management? May 2012. The ToolKit? September 2011.

So was Dr. Belay simply mistaken, and the 2012 updates reflect the revisions made with CFSAC’s input? Or are the changes still trapped in CDC internal review? I have no idea. Someone should have asked.

Wordsmithing

I asked my husband last night if it was reasonable for senior-level people to present rough draft recommendations for a full committee to wordsmith together. He said he would be fired on the spot if he did that in his field. But wordsmithing by committee is precisely what happened for roughly two hours of the CFSAC meeting.

wordsmith1It wasn’t clear from Dr. Levine’s presentation whether she drafted the recommendations on her own, or if the working group had collaborated on drafting them. Whatever the working group’s process, it was abundantly clear that the draft was not ready for prime time, thus leading to the two hours of refinement.

Lack of clarity was pervasive throughout the recommendation language. What disease are we trying to educate doctors about? How should we define integrative medicine? Do we mean physicians or medical professionals? And on and on and on. The committee spent two hours hammering out all this stuff that could have been done partially in advance. FACA requires that the recommendations be discussed and approved in public. It does not require that they be written by the full committee in real time during a public meeting. There is no reason why the working group could not have spent two hours working out the details and supporting evidence, and then present a more polished version to the full committee. Non-working group members would still have a chance to ask questions, offer changes, etc.

I’m not saying the refinement was poorly done. The final version approved by the committee was significantly improved by the group effort. It was essential to replace verbs like “suggest” and “support” with verbs like “recommend” and “fund.” It was also essential to identify what supporting documentation and evidence should be submitted to the Secretary with the recommendations. My point is that these things could and should have been done before presentation to the committee. Not only was it frustrating and inefficient, but the time spent on this process meant that there was NO time for discussion of future issues for working groups and recommendations. A very large item of business was left unfinished.

So what did the committee actually recommend? Basically, the committee recommended that HHS fund the development of curriculum at medical schools, fund teaching modules featuring complex cases, support integrative medicine programs featuring learning about ME/CFS, fund novel programs to bring expert care to under-served areas, gather requisite data for established organizations to incorporate ME/CFS in education, and support the CFSAC effort to amend the CDC website. All of these recommendations were explicitly worded to focus on ME/CFS as defined by the 2003 Canadian Consensus Criteria.

What was missing was a statement of the case. Yes, multiple supporting documents were identified, including the 2003 Canadian Consensus Criteria, the Primer, and the Expert Letter to the Secretary. But the Secretary is (or should be) already familiar with those documents. HHS has already declined to follow the Expert Letter or to remove the CDC Toolkit. Why should the Secretary listen now? In order to create a compelling argument for these recommendations, the working group should have prepared a one page statement of the case. That case could present the data on medical school education and the responses the working group got when they contacted the professional associations (which boiled down to “prove to us this is a public health problem”). They should be sending the Secretary a few paragraphs that convey not only the urgent need for better provider education, but also why the current efforts are inadequate. Instead, the committee is apparently deferring that to Dr. Marshall, who will write the cover letter accompanying the recommendations. Will everyone on the committee be satisfied with what he writes? I hope so, since they delegated the task to him and did not ask to see a draft version before it goes to the Secretary.

Widening Divide

The public comments raised an issue that is increasingly troubling to me. Dr. Jon Kaiser (founder of K-PAX Pharmaceuticals) closed his remarks with strong praise for all the federal agencies and their efforts on ME/CFS. Bob Miller cited four examples of how he sees the federal government “turning a corner” on ME/CFS, although he pointed out that results will be the ultimate measure of success. The rest of the public comments took HHS and CFSAC to task for lack of progress, or worse.

There has always been a divide in the ME/CFS advocacy community between advocates who thought the government was making progress (albeit slow and inconsistent) and those who thought the government was stalled or moving backwards (perhaps intentionally). But it seems to me that this divide has grown significantly wider in the last year. I’ll be writing more about this soon, so I’ll just put a pin in the topic to save it for later.

The Silver Platter

The disconnect between the accountability and progress that ME/CFS patients deserve and the decisionmaking put on display at CFSAC meetings remains large. These meetings are so frustrating, and increasingly so, that it is easy to see why some people believe HHS is doing this on purpose. Maybe they blame individuals, maybe they blame the Department, maybe they blame a highly placed policy maker, but many ME/CFS advocates believe that the sheer volume of problems can only be explained by intentionality.

WhitegloveSilverPlatterSizedHow else can we explain a repetition of technical difficulties from the December meeting? How else can we explain the CDC’s failure to be forthcoming about their own website? How else can we explain the conduct we see in these meetings, and the way CFSAC’s recommendations are handled by the Department? How else do we explain the lack of urgency?

I have no explanations to offer. But somebody could, and should. FDA has consistently demonstrated over the last two years that it is listening to patients and advocates. FDA has held open teleconferences and given advocates the freedom to ask questions and make their points. FDA held the public meeting last year, and followed through on its commitments to produce summary reports and draft guidance to industry within a year. Advocates do not agree with all of FDA’s decisions by any stretch of the imagination (e.g. Ampligen), but we recognize that FDA is listening and moving forward.

That is what progress looks like. And the contrast with CFSAC could not be more stark or more troubling.

 

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Guidance to Industry

Posted on March 10, 2014 by Jennie Spotila

Last year, the FDA said it would be preparing Guidance to Industry on drug development for ME/CFS and now they have delivered. Guidance for Industry Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: Developing Drug Products For Treatment* has been published in draft form, and the public has 60 days to submit comments. In this post, I will simply summarize the draft guidance. I hope to post more detailed analysis later this week.

FDA’s Guidance for Industry documents are intended to capture FDA’s thinking on a topic, including drug development for specific diseases. The need for such guidance was put on display last year in the FDA’s denial of approval for Ampligen and in discussions at the April PFDD and Drug Development meeting on ME/CFS. While Guidance documents are not legally binding, they do convey a sense of FDA’s preferences and how it might approach the drug review process for ME/CFS treatments. Here’s what stood out to me in my review of the document:

Unmet need: FDA says “CFS/ME is a serious disease and there is unmet medical need in the treatment of CFS/ME.” This represents “a public health concern.” (page 3) This means that drugs for ME/CFS may qualify for one or more of the expedited review programs.

What is it: Consistent with earlier statements, FDA is using CFS/ME to refer “to a disease or set of diseases.” (page 2) FDA is not taking a position on exactly what disease or diseases is covered by this Guidance, so it can include CFS, ME, or ME/CFS. The document includes a list of symptoms, and notes that post-exertional malaise and cognitive impairment are particularly severe for patients.

Defined as: FDA is also not taking a position on the suitability of one or more case definitions, also consistent with earlier statements:

At this time, the FDA does not recognize any particular disease definition, nomenclature, or diagnostic criteria for CFS/ME as the most appropriate for use in clinical trials of new drug products. Consequently, any case definition or criteria for CFS/ME can be used to define the patient population. (page 3)

Patients with confounding conditions that cause fatigue and related symptoms should be excluded, and sponsors should define whether the target population is a “general CFS/ME population or a subset.”

Endpoints: Efficacy endpoints should include patient-reported symptoms, and may include objective measures. A single primary endpoint with supportive secondary endpoints will be sufficient. Biomarkers can be used as “exploratory endpoints,” but primary endpoints must reflect benefit in how the patient feels and functions. In other words, patients have to feel better; change in a biomarker is not sufficient on its own. (page 4)

Other treatments: A placebo group does not need to preclude usual care treatments, and “patients enrolled in the trial should be permitted to use concomitant treatments as needed to manage disease symptoms.” (pages 4, 6) The treatment design must take this into account.

What is effective: The sponsor must demonstrate substantial evidence of efficacy in CFS/ME symptoms. Since no PRO instruments are optimal for measuring fatigue or other symptoms of CFS/ME, FDA will consider using instruments validated in other conditions. This is good news, because it means developers do not need to wait for FDA to validate PRO instruments specifically for ME/CFS. (page 5)

Post-exertional malaise: FDA recognizes that post-exertional malaise and exercise capacity are two different potential areas of treatment benefit. Either exercise testing or PROs measuring post-exertional symptoms can be used to measure efficacy of treatment, recognizing that some tools would not be appropriate for severely impaired patients. (page 5)

Quality of life: As for general measures of effectiveness, FDA will consider health-related quality of life measures validated in other conditions. Direct evidence of improvement in a patient’s performance of work, household, and personal tasks can demonstrate treatment benefit. (page 6)

How long: Given the chronic nature of CFS/ME, treatment trials must last at least 24 weeks, and possibly longer. Two definitive trials showing efficacy should be sufficient. Long-term safety trials must be conducted, given that treatment is likely to be prolonged. (page 6, 7)

Combos: A new drug product can include a combination form of two or more individual drugs. This is important because several clinical trials of combination therapies are in the works. In addition, a drug product that requires a specific accessory (like an injector) must ensure the device is approved as well. (page 7)

 

*Credit to @mrkipping on Twitter for putting out the first notice I saw about the document. Disclaimer: I am a member of the FDA’s Patient Representative Program. However, this post represents my personal opinions and are not comments made in any official or formal capacity.

 

Posted in Advocacy, Research | Tagged , , , , | 13 Comments

Systematic Overreaching

Posted on March 6, 2014 by Jennie Spotila

Reaching_Arm_3_by_DecepticoA study published last month* by a group from Norway reports a systematic review of ME/CFS case definitions. It’s important because the Institute of Medicine panel is likely conducting a similar process as part of its work, but the study is also significant for the startling and overreaching conclusions drawn by the authors.

Quick Summary:

  • This study collects and examines case definitions for ME/CFS, and extracts prevalence data. This will be a helpful future reference.
  • The authors then step far beyond their own evidence and draw a variety of overreaching conclusions.
  • Future analysis must be wary of cognitive bias in order to avoid the same mistakes.

What They Did

Brurberg et al began by searching the literature for case definitions of ME/CFS (a term encompassing CFS, ME, and combinations of the two). The group then looked for validation studies, meaning studies that applied one or more case definitions to patient populations. Of the twenty case definitions identified in the first step, seven have never been validated in a patient population. Thirty-eight validation studies were identified that test one or more case definition, but the authors were very critical of the quality of those studies saying, “We did not identify any study which rigorously assessed the reproducibility or feasibility of the different case definitions.”

The authors categorized the validation studies, and the summaries and Tables 1-4 are actually quite helpful. Five studies independently applied several case definitions to a single patient population, and thirteen studies took patients diagnosed under one definition (usually Fukuda) and sequentially applied case definitions assumed to be more specific. The authors caution that this second group of studies “should be interpreted with great caution” because there were so many differences in diagnostic method and definition application, including different thresholds for exclusion of psychiatric comorbidity. Finally, twenty-one studies presented prevalence estimates and the authors extracted data on prevalence rates for Fukuda, Oxford, and the Australia 1990 case definitions.

Personally, I find the collection of these studies and extraction of data to be both interesting and important for future reference. I think it is very likely that the IOM panel is conducting a similar review of the case definition literature, as well. Rigorous examination of case definitions and their applications is essential for the IOM and for the ME/CFS field in general. Brurberg et al found this body of evidence to be “methodologically weak and heterogeneous, making it questionable to compare the case definitions.” What I found both startling and disturbing is that the authors then go on to draw a number of conclusions that are simply not supported by the evidence they examined.

Insupportable Conclusions

First, the authors state, “We found no empirical evidence supporting the hypothesis that some case definitions more specifically identify patients with a neuroimmunological condition.” But they didn’t look! The validation studies they examined applied case definitions, but frequently by questionnaire or retrospective analysis. The studies examined by the authors did not take a group of patients, separate them by case definition, and then look for signs of a neuroimmunological condition. There are studies that do conduct such experiments – testing for immune markers, gene expression response to exercise, etc. – but the authors did not look at those studies because their systematic review was not designed to capture them. It’s overreaching to conclude that something doesn’t exist when you didn’t actually look for the evidence to begin with.

Second, the authors argue that for clinical purposes, a broad definition can be helpful because it identifies more patients who may benefit from treatment. They point to the PACE trial as showing the effectiveness of CBT and GET “irrespective of the case definition which had been used.” But they fail to mention some of the PACE follow-up papers, including this one in which the PACE authors admit that the application of the CDC definition in assessing recovery “may have been inaccurate because we only examined for accompanying symptoms in the previous week, not the previous 6 months” as required by the CDC criteria. This is just one example of the many documented methodological problems of the PACE trial, all of which are ignored by Brurberg et al. A glaring example of this is the statement that “existing evidence indicates that side effects of cognitive behavioural treatments or graded exercise therapy are negligible.” This conclusion ignores analysis by Tom Kindlon of the problems with reporting harms in studies like PACE, and published data from trials that did not find treatment benefit for CBT/GET.

Third, the authors argue that the organic vs. psychic disorder debate should be abandoned because most medical disorders have a complex aetiology, and psychological treatments can have benefit in “clear-cut somatic disorders.” But they then point the finger at patients: “Unfortunately, patient groups and researchers with vested interests in the belief that ME is a distinct somatic disease seem unwilling to leave the position that ME is an organic disease only. This position has damaged the research and practice for patients suffering from CFS/ME.” This statement is patently outrageous simply on the basis of logic. They present no evidence to support their accusation that the organic disease-only position has damaged research and clinical practice. Furthermore, they completely ignore the very real and logical possibility that the reverse is true! In other words, it is equally possible that the the people with vested interests in the belief that ME/CFS has psychosocial causes are unwilling to leave that position, and have damaged the research and practice for patients suffering from the disease. I can present ample evidence that this is the case, but the authors seem to dismiss the hypothesis outright.

Fourth, the authors conclude that, “Development of further case definitions of CFS/ME should be given low priority.” Instead, “Priority should be given to further development and testing of promising treatment options for patients with CFS/ME.” How is it possible for effective treatments to be developed if there is not an accurate case definition to identify patients for the studies? The authors admit that classifying severity and symptom patterns to identify potential predictors of treatment benefit “might be useful.” I would say that such work is essential. Furthermore, given the strong methodological criticisms of validation studies raised by these authors, their analysis seems to support a strong argument for further work on validating and refining case definitions, rather than throwing up one’s hands and working with what we’ve got.

Conclusion

Overall, the authors’ collection and review of the ME/CFS case definitions and validation studies will be very useful as a future reference. But they leap far ahead of what their review data suggests, and draw multiple conclusions with little or no supporting evidence. By failing to correct for their own cognitive biases, the authors allow assumptions to contaminate their conclusions.

The IOM panel, AHRQ systematic review, P2P Panel, and other researchers must be mindful of this in conducting their own analyses and drawing conclusions. Otherwise, we are at great risk for the cognitive bias and overreaching of Bruberg et al to become embedded in the literature and accepted as true.

 

*Brurberg K, Fonhus MS, Larun L, Flottorp S, Malterud K. Case definitions for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a systematic review. BMJ Open2014;4:e003973 doi:10.1136/bmjopen-2013-003973

 

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Yay, and Also Boo

Posted on March 3, 2014 by Jennie Spotila

Yay! The CFS Advisory Committee will meet on Tuesday, March 11th from 12-5pm. This is the makeup day for the meeting cancelled on December 10, 2013. Boo! This is another webinar, and one can only hope the technical aspects will be smoother than the mess in December.

Yay! Registration is not required for this webinar. Boo! No instructions have been posted for joining the meeting.

Yay! The agenda is available. Boo! The minutes from the December 11, 2013 meeting are not.

Yay! The public comment originally scheduled for December 10 has been placed on this meeting’s agenda. Boo! No other public comment – including written comment – is being accepted for this meeting.

Yay! We will hear updates from the agencies who did not present at the December meeting. Boo! We are not scheduled to hear anything from NIH and CDC – which means no update on the multisite study or the P2P meeting. Given the importance of both, this is a gaping hole in the agenda.

Yay! We will hear more from the two working groups. Boo! It remains to be seen if they have made significant progress in the last three months. I hope so.

Yay! I’ve been told there will still be a “spring meeting.” Boo! No idea when that will be, whether it will be in person, etc etc etc. Edited to add: An email on the CFSAC listserv dated November 12, 2013 stated that spring 2014 CFSAC meeting will be an in-person meeting.

Yay! CFSAC meetings are, at the very least, a chance to learn more about what is or is not being done at the agencies. Boo! There is no time on the agenda for public Q&A, so we have to rely on the CFSAC members to ask the right questions. This has been a problem in the past. In fact, the lack of questions from members means that many issues are discussed at one meeting and then never followed up on at subsequent meetings. Case in point: CFSAC asked to see copies of the CDC’s revised Toolkit prior to its release, and further suggested that a black box warning regarding exercise be placed on the CDC’s website. There has never been follow up on the record for either issue.

As an aside, I refreshed my memory of the December meeting by rereading my commentary and I had forgotten how disastrous that meeting was. It’s hard to imagine next week’s meeting being worse, but I’m also not getting my hopes up. CFSAC has a long way to go to make up for the deficiencies of the December 2013 meeting.

 

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Viral

Posted on February 28, 2014 by Jennie Spotila

131016160943-01-vintage-flu-story-topI had it all under control. After coming down with a virus (mild flu?) in January, I got the message and seriously scaled back my activity. Joe Landson, Denise Lopez-Majano, and Claudia Goodell all came through for me in a big way, and shared tremendous guest posts to give me time to recover.

It took close to three weeks, but I clawed my way back to what my friend Trina Berne calls “Normal Shitty Baseline.” I felt my brain waking back up, and was able to start cooking dinner again. Then earlier this week, my husband came down with flu-like symptoms plus sinus infection symptoms. He went on Tamiflu and antibiotics, and while the drugs have helped, he has been pretty sick and miserable all week.

I bet you see where this is going. My nasal congestion and sore throat returned yesterday, and I woke up at 5am with a fever. Now I’ve got a call in to my doctor to see if I need Tamiflu. Because really, this is exactly what I needed to happen now. NOT.

What’s weird about it is how different this is from my usual ME/CFS pattern. For most of the last 19 years, I haven’t caught upper respiratory infections very easily. My husband gets several a year, but I almost never catch them. I know many patients are susceptible to any infection that comes along, but I seemed to be in the category of patients who were not. I always attributed it to a heightened immune response connected to ME/CFS.

Catching two bugs in a month is extremely unusual for me. It could be random chance, of course. But as with most symptom changes, I always wonder: is my ME/CFS changing? Is my immune system starting to break down after almost two decades of illness? Will this be the new normal?

Hopefully, I won’t get as sick as I did last month. Hopefully, I’ll be able to follow through on some of the posts I have planned for March. Hopefully, this is just a glitch and I won’t be dealing with fevers and congestion all the time.

Because life with ME/CFS can be miserable on a good day, and dreadful on bad days. Because I hate being held hostage by my body. Because I am already so limited by this disease, I resent the hell out of anything that limits me more. Because I would rather be writing.

 

Posted in Occupying | Tagged , , , , , , | 20 Comments