Saturday, April 27, 2013

Thoughts on FDA Workshop April 2013

Some thoughts on the FDA Workshop on M.E and CFS

As often happens when I attend a government meeting on our disease, I am left with more questions than answers.

The purpose was to facilitate drug development for our disease, and I don't think we made very much progress there.  There's always someone to say "no," to put down an idea.  It gets frustrating.

So here are some random impressions that could be productive:

1.  We were informed there is money at NIH to develop and validate tests, questionnaires, and endpoints for drug testing.  If you could get something verified, the drug company can just go ahead and use it.  Otherwise, they don't have much to go on.  Perhaps patient groups should think about tests that should be verified and getting this accomplished.

2.  In the absence of validated tests, particularly biomarkers, we're left with questionnaires.  Questionnaires pose a LOT of problems, but more so with our disease because cognitive dysfunction is a primary symptom.  I think FDA was beginning to "get" this.  We should use that to emphasize the need for objective testing.

3.  Sometimes we can be our own worst enemies.  We need whatever biomarkers we can get.  There were patients complaining that VO2 MAX testing is unethical.  Well, just how are you going to show the significance of our disability without walking on the edge?  Off Ampligen, my VO2 MAX score is 14-15 - which is in the seriously disabled, dangerous range.  (More on that later.). But I'd do it tomorrow if it meant someone would take our symptoms seriously, or I could get a drug passed.

4.  I don't know how to get around this one, but those of us who have been really sick for a very long time may require a long period of treatment before we show much improvement.  That's expensive.  But it needs to be taken into account nevertheless.


Now, those were thoughts on testing for drug approval.  Here are a few things that occurred to me just listening to what was said.

1.  IT'S ALL ABOUT THE DEFINITION.  I think that's self-evident to anyone reading this, but it about drove me crazy on the second day.  I do not want to be in a "cooperative" data sharing effort with someone (e.g., the CDC) who uses the Reeves or "empiric Fukuda (2003)" definition.  I want to be in studies that use the M.E. (2011) international research definition or the M.E./CFS (2003) Canadian consensus definition.  For those of you in the UK, that means beware of a research program being set up that cooperates with those who use the Oxford definition.  It will really skew the results because the ill-defined Oxford cohort will outnumber and swallow up any group defined by a more biomedical definition.  When it comes to drug approval, we need to convince drug companies to go for a definition that gives you the most homogeneity.

2.  What is the REAL meaning of those VO2 MAX (CPET) scores?   Everyone talks about using the VO2 MAX stress test to prove disability, or using the 2-day version to demonstrate the biological nature of post-exertional collapse.  But I want to take this a step further.  I knew I was really sick, but I was honestly shocked at how low I scored on that test.  WHAT DOES IT MEAN TO SCORE 15 OR BELOW ON A VO2 MAX STRESS TEST?  It means THERE IS SOMETHING SERIOUSLY WRONG WITH YOUR CARDIOPULMONARY FUNCTION.
     To push this further, when I scored so badly I had a mess of active viruses in my blood serum (EBV, HHV-6A, CMV, HHV-7, and Coxsackie B).  I had active CMV and HHV-6A in my spinal fluid and classic symptoms of encephalitis, so I think it's a good bet that I had viral encephalitis.
     But did I also have viral myocarditis?  Lenny Jason has suggested we are more likely to die of a heart attack prematurely than die of suicide.  IS THERE MORE CARDIAC DAMAGE IN THS DISEASE THAN RESEARCHERS HAVE REALIZED?  How do we get someone to pay attention to this information?
     [For the record, most of the encephalitic symptoms clear up for me within six months on Ampligen.  But my CPET scores don't budge for at least a year.  Then they do start getting better, and after 4 years on Ampligen my CPET score was actually normal.  Perhaps that helps explain why it seems to take much longer to get my stamina back.]

3.  Where is the rest of the iceberg?  How many years have we been told that only 15-20% of patients with this disorder have a diagnosis?  Where is the 80-85%?
     Someone asked a panel about the distribution of this disease by ethnicity.  Beth Unger of CDC responded (and I agree with her response) that evidence shows this disease is at the equal opportunity - and that African-Americans and Latin Americans may actually have a slightly higher prevalence rate.
     THERE WERE NO PEOPLE OF COLOR AT THIS CONFERENCE (AFAIK) except for one person who was not a patient.  People of color are grossly under-represented in the diagnosed population; I don't want to think how badly they are represented in the practices of the handful of specialists who actually know what they are doing.
     Could we find out?  Could we get an accounting from the clinician experts as to what percent of their patient population with this disease are white?  How about income?   I think we already know the answer to this.
     WHO WOULD BE INTERESTED IN THIS PROBLEM?  Are there political groups who might be interested in the neglect of patients of color?
     And WHERE ARE THE 80-85%?  I was an invalid.  Someone would have had to take care of me, and someone did.  What happens to a single mother of two when she gets a serous case of this disease and remains untreated?
     What has happened to patients I knew well online in the 1990s who have just disappeared?

The larger question, of course - the elephant in the room - has yet to be addressed by anyone in the government:

WHERE IS THE SENSE OF URGENCY?  What is it going to take to hear that word spoken by someone in a position to actually change things?


  1. Thank you Mary. You express one of my fears and several of my concerns. My V02Max was under 15 and as a result, I had a heart cath and some other top drawer testing. My heart is fine, but there are so many others who have not had the opportunity to have a VO2 MAX to show terribly low scores and the symptoms are ignored. So what if when you get to the top of a short flight of stairs, your heart is pounding, you are short of breath and feel lactic acid burn? Must be de conditioning. Most medical facilities anywhere near a sports complex have V02 max equipment. It is not a stretch to have people with ME symptoms just do the damn test. It is not a pleasant test, but it is not horrid either. Believe me, the local doc's ordered all those cardiac tests once they saw my VO2 max. It was not me. An ethical responsibility to look further when a person's VO2 Max looks like heart failure involves some medical oversight problems, hey?

    Concern. The 80%. It is the elephant in the room. Many local doctors do not want to look further with multi symptom illness. Over my 25 years of talking with patients on the phone, I know really sick people on many meds just get more ill and are told that, oh, well, what they say they feel is to be dismissed. JUST TAKE THIS PICK ME UPPER, I was told once. BUT I HAVE ACCESS. I can find information and I ask a lot of questions about medications. PICK ME an SSRI and I am serotonin sensitive..makes me horribly ill.

    Back to the point. With more than 25 years behind us, illness bias is entrenched. BIAS, STEREOTYPING and the treatment that follows has not affected me because I am informed, but so many people I talk to do not have a clue what they are up against. NIAID had a toll free number where a patient could call to get more information. Too many calls, too much money.

    AS usual it will be up to us to find ways to get to the 80%.

    1. Pat, you and Mary have been involved in advocacy far longer than many others, but based on my comparatively limited experience the FDA meeting in some ways made more strides in a day and a half than has happened in many years.

      Of course we still don't know whether Big Pharma will be interested and new drug creation (approx 15 years) may be too late for many current patients, but may save another generation.

      I would say there is now a better base for meaningful progress. It takes awhile to turn the equivalent of the Titanic.

  2. FWIW, I recall seeing a tweet that 95% of one group of patients (I think it was those attending the clinics the CDC is surveying) were white. Perhaps not representative of the population in terms of race. But I prefer these studies to the random population, (so-called) empiric criteria studies.

    1. About 2 1/2 years late with this answer, but the 85% figure comes from demographic studies conducted at DePaul University by a very good group, run by Leonard Jason, an academic psychologist who is also a patient. They had translators for the most common languages in the Chicago area (where the study was conducted). Most studies use the resulting publication from 1999 for the best estimate of prevalence of the disease. To use it today would suggest that the prevalence has remained the same - my suspicion is that both prevalence and absence of diagnosis have increased, but we'd need a new study to know for sure. It does give a lower bound (that is, at LEAST that many people have it).

      At any rate, this was very professionally done. After all, there is no medical reason why this disease should impact whites more than non-whites. If 95% of those attending CDC clinics are white, that is an example of the precise problem. The percentage of non-Hispanic white people in the US today is 63% according to the US census. Put another way, 37% of the patients attending clinics surveyed by CDC should have been non-white. That suggests that underdiagnosis is much more common in the non-white, non-Hispanic population of the US.

      Those studies may be just fine for the purposes intended (looking for biomarkers, for example). But CDC - the Center for Disease Control, after all - should be looking for those 850,000 undiagnosed patients, and they have not and are not.

      My suggestion was to note that perhaps we could get help from organizations that deal with the health of patients in different ethnic groups in finding at least some of those undiagnosed patients.

  3. I was thinking this morning about the needed length of clinical trials involving long-term patients, too, Mary, with my daughter's response to high-flow oxygen being a case in point. She'd been ill for 13 years before trying it, severely ill for 7, but is also in her 20s, so presumably has some youthful oomph going for her. Even so, it was months of using it daily before the improvements passed the "just noticeable difference" level. She's 19 months into using it and it seems like she's having cascading improvements now -- that the pace has picked up substantially in the past 3 months. But who would be willing to fund a 2-year clinical trial with only barely noticeable improvements during, say, the first 6 months of treatment? (Obviously, no-one will fund a clinical trial of high-flow oxygen because there's no money to be made from it.)


  4. As far as I can see, the primary issue here is this:

    Clearly, some of the treatments that doctors/researchers have developed for CFS do work. Sometimes they work really impressively. Even the FDA said so, at the meeting a few months ago when they declined to approve Ampligen.

    The problem is not that we don't have treatments that work. It's that we don't have treatments that work consistently enough that we can legitimately insist that government agencies in all good conscience MUST approve them.

    If treatments only work a fraction of the time, and we can't predict when those times are going to be, then our case for getting people to do what we want is very very weak, no matter how good our rhetoric or lobbying skills are.

    So what I would like to see is more stakeholders (researchers, doctors, patients and advocates) focusing attention on what it is that is causing these treatments to work some of the time but not all of the time. If we don't clearly start asking the question and trying to figure out the answer, we're never going to get anywhere -- or at least, so our 30-year history so far would suggest.

    As a starting point, here is a new paper by Dr. Ritchie Shoemaker, on a treatment called VIP. (The fact that this is with a population of chronic mold illness patients is irrelevant here -- Dr. Paul Cheney now says that there is no difference clinically between "CIRS" patients from WDB's and his own CFS patients, and the other main CFS doctors have pretty much all acknowledged a mold connection to this disease too.)

    One thing that Shoemaker makes clear in various places (though not in this paper itself) is that VIP only works when people are living in a non-moldy environment (e.g. with an ERMI test showing it is in the top 1/3 of all buildings). If people are in a moldy place, VIP doesn't help at all. So for this paper, he only used established patients who already were living in good environments -- those still living in bad buildings were not included.

    Is it possible that the reason that -- say -- Ampligen works only some of the time but not all of the time is because it only works when people are living in reasonably decent places?

    Could it be that this is also true with other treatments such as Rituximab or Valcyte?

    If we don't know the answer for sure one way or the other, might it not be time to start asking?

    From a personal experience point of view (e.g. the kind that Ampligen responders wanted the FDA to attend to), I've now tried a lot of treatments in various conditions (good environment vs. bad environment). And I believe very strongly that at least for me, all the things that are supposed to help with CFS actually do help. But at least for me, they only help when I'm in a decent place. A really bad environment trumps everything else.

    Based on the increasing number of mold avoiders (dozens and dozens) who are reporting back to me on their own experiences, the same thing appears to be the case for other people with CFS. In a good environment, lots of things help people with CFS. In a bad environment, nothing helps.

    Thus, I would like to see CFS researchers and clinicians start to use mold-related measurements (such as the ERMI test or C4a test) as independent variables in their studies.

    If by chance we can prove that some treatments actually do work consistently, under the right environmental conditions, then we will be in much better position to go back to the FDA to try to get those treatments approved.

    Thanks for your report on this meeting, Mary.


    Lisa Petrison, Ph.D.

  5. I too wonder if the current CDC collaborative (which is not a bad thing in all ways) is not missing two important groups of patients.

    The first might be the long term patient who has given up on doctors/run out of insurance and just doesn't go anymore - at least not for ME and CFS.

    The second Mary also mentions - is the CDC clinician collaborative missing ethnic/socioeconomic variables that might be important?

    For example, poor patients and those least likely to be able to see a specialist may also have more stress and as the ICC among others points out - stress exacerbates symptoms. So is it possible that they are sicker than some? In terms of ethnicity, there are multiple diseases that hit some ethnic groups harder than others.

    Don't know if you don't study the demographic and guessing shouldn't be good enough.

  6. There seem to be several biomarkers already in play "out there," including the VO2Max testing, what would it take to get one or more of these accepted? Maybe I'll answer my own question - clinical trials?

  7. I asked the FDA by emails and letter to consider liasing with other government bodies including the CDC, the NIH and the US Department of Health with the objective of establishing a new system for

    (i) diagnosing ME/CFS. The Canadian Criteria (2003, 2011)
    (ii) measuring biomarkers for the abnormalities, dysfunctions and infections found in ME/CFS patients. Some ideas are presented here
    (iii) treating these abnormalities, dysfunctions and infections. Some ideas are presented here
    (iv) tracking progress in doctor / GP settings and in research trials. Some ideas are presented here
    (v) standardisation of research methods and critera for ME/CFS across America and the world, so that replication of studies is more precise, consistent and accurate
    (vi) stating what constitutes improvement and what constitutes full recovery in objective scientific terms
    (vii) a biological database tracking all stages of recovery for ME/CFS using biomarkers and objective scientific evidence
    (viii) The FDA could work with Biovista’s ME/CFS progam ( ) in the USA. Biovista is engaged in research and data mining of thousands of medical drugs (including some which are currently out of use) and finding matches between them and the symptoms, abnormalities and dysfunctions found in ME / CFS. They are compiling a list of these medical drugs with the objective of having these dugs re-purposed for ME/CFS treatment.
    Some of these ideas, and scientific and medical facts are discussed on the Cross-border ME clinic proposal at
    This new system, numbered (i) to (viii) above would impart greater precision to drug development, drug re-purposing and drug use in ME/CFS patients. This would enable the FDA and other Federal bodies to make swift and effective progress in relation to ME/CFS. This would benefit ME/CFS patients in the USA and over time, by diffusion of new standards, criteria and knowledge, benefit ME/CFS patients all over the world.
    David Egan