MEadvocacy would like to thank advocate Eileen Holderman for her consultation on this blog post.
MEadvocacy sent a petition to NIH to cancel and restart the NIH Intramural Study on ME/CFS because of the many significant problems with the study’s design and protocol and lack of myalgic encephalomyelitis (ME) stakeholders’ input.
Since then, NIH has used various and confusing ways to communicate new and changing information about the study. As further information became available, we voiced our deep concerns about many of the significant issues with the study: multiple and ever-changing criteria, some of which are deeply flawed; biased and/or inexperienced investigators and advisors; additional problems with the study’s design; mistrust of the government health agencies and the problems with the way NIH is communicating.
This is a unique opportunity to design a robust study using the comprehensive resources of the NIH Clinical Center. It is crucial that this study be done with ME experts' and stakeholders' input from start to finish. This will ensure meaningful results and scientific advancement for patients who suffer from this serious, disabling disease.
The MEadvocacy petition with 725 signatures was initiated on February 9, 2016, and sent to Dr. Francis Collins, Director of the National Institutes of Health (NIH), on February 15, 2016.
The petition called for:
Rejection of the Reeves’ criteria and its associated questionnaires
Restart of the NIH clinical study using a protocol pre-approved by ME experts and stakeholders
Transparent communication to the patient community
On February 23rd, we sent a follow-up reminder with additional concerns about the study:
NIH chose a lead associate investigator, Dr. Brian Walitt, with a psychosomatic viewpoint of the disease
The selection of recovered Lyme disease patient group (a disease fraught with controversy) as a comparison cohort
The selection of functional movement disorder patient group (a disorder that falls under the mental illness classification of somatoform disorders) as a comparison cohort
On March 11th, MEadvocacy received a reply to our petition from Dr. Koroshetz. However, Dr. Koroshetz’s reply and NIH/NINDS’ actions sidestepped our crucial concerns.
The Ever-Changing Criteria
Why is Research and Clinical Criteria Used for Patient Selection So Important in ME?
Many diseases have testable biomarkers for use in selection of patient cohorts in studies. This ensures that the correct group of patients are being looked at. This is not the case with ME. To date, a testable biomarker has not yet been accepted. Therefore, it is of utmost importance that the strictest criteria (ICC or CCC) be used in studying ME in order to ensure that investigators are looking at a homogeneous patient cohort.
Historically, the criteria issue has been a grave problem with research into ME because various vague criteria have been created and used. Overly broad CDC criteria, such as Reeves and Fukuda, include patients who have: chronic fatigue, idiopathic fatigue, somatoform disorders, major depressive disorders, and other unrelated conditions. CDC has created the problem of heterogeneity of the disease and caused the commingling of cohorts. For three decades, they have served to obscure the original findings of ME outbreaks which has led to the suffering of a million American men, women and children.
Timeline of Criteria Changes
From the time NIH posted the first protocol showing the Reeves’ criteria on their website, it has been a fiasco of continually changing criteria and news.
First, the initial protocol posted on the NIH website became public with what we were later told was incomplete information. This protocol showed that Reeves’ criteria would be used to select the patient cohort. Furthermore, the NIH website code reveals that changes had been made to the protocol at least two times, which makes it hard to believe that it was ‘mistakenly posted’ in order to achieve a study number, as stated by NIH (see details here).
Days later, the initial protocol was removed and NIH did not post a reason why it was removed.
Later that day, an advocate posted a notice on a website stating that NIH informed them of the following: “Enrollees will meet all definitions for ME/CFS, including Canadian Consensus Criteria, IOM, Fukuda and Reeves, in addition to post-infectious onset.”
A week later (about an hour after MEadvocacy’s petition was delivered to NIH), Dr. Koroshetz sent an email to a select few advocates, stating that patients will: “...qualify under multiple consensus criteria including the Canadian criteria. Reeves was being used only for stratification purposes.”
The next day (after Koroshetz sent his email), Dr. Nath informed the public during his CDC Grand Rounds presentation that the NIH study would use two criteria - Fukuda and CCC - for selection of patients (see slide #53 here).
Three weeks later, at the NIH Telebriefing, none of the four NIH presenters mentioned criteria. However, it was announced that a new website for the study went up that morning which shows one specific criteria to be used - the CCC (item #1 on FAQ page).
The most recent letter to MEadvocacy by Dr. Koroshetz now states that two criteria - the CCC and IOM will be used for selecting patients (3rd paragraph).
The Need for Real ME Experts in the Study
In his March 11th letter to MEadvocacy, Dr. Koroshetz states: “As you may know, the NIH study protocol is still being revised. It is being developed with guidance by experts from a number of disciplines and is intended to be the most detailed physiological analysis to date of patients who developed ME/CFS following an infection.”
Dr. Koroshetz sidesteps our request for ME experts and patient advocate involvement with the study design and protocol from the beginning. He responds with the information that experts from a number of different disciplines were involved in the guidance, but doesn’t state that they were experts specifically in ME.
If ME advocates would have been involved from the beginning and given power of approval, Drs. Brian Walitt, Fred Gill and Leorey Saligan would not have been put in charge of assessing diagnostic validity for selecting and managing patients in the clinic.
The Inherent Bias of the Lead Associate Investigator and Those in Charge of Patient Selection
The FAQ section of the NIH study website states the following: “Most patients will be recruited from well-established ME/CFS clinics that are being supported by the CDC in the Multi-site Clinical Assessment of CFS study.”
It says “most” but not all. This is very troubling because we don’t know what they mean by “most”. For instance, does it mean 25 patients will come from the ME/CFS clinics and 15 will not? Where will those not coming from the ME/CFS clinics come from? Furthermore, the website instructions state that one can register online to become a participant in the study. Where are those patients coming from?
The final assessment will be done by “clinical experts at NIH, including Drs. Fred Gill, Leorey Saligan, and Brian Walitt” who have inherent and common biases about the disease. We do not believe the selection of these specific NIH researchers, who have the same inherent bias, is a coincidence, but rather an indication of the path this study was intended to take.
NIH Intramural Study on ME/CFS website - FAQ section
Dr. Brian Walitt has been selected by NIH as lead associate investigator for the study, as well as part of the committee selecting the patient volunteers. Much has already been written about the concerns of having a lead associate investigator who believes fibromyalgia and chronic fatigue syndrome (CFS) are psychosomatic and somatoform disorders. In September 2015, Dr. Walitt gave an interview at a rheumatology conference on fibromyalgia which advocate Jeannette Burmeister blogged about. It is troubling that Dr. Walitt will be responsible for administering the subjective questions/questionnaires by phone and in person at the clinic.
Below are just a few studies Walitt has been involved with:
Dr. Fred Gill worked with the late Stephen Straus, NIH virologist who ignored the biological evidence of ME in favor of a psychological view which set the tone for decades to come, as noted by advocate Dr. Mary Schweitzer in her blog. In a letter (part 1 and part 2) Dr. Straus wrote to Dr. Fukuda, he laid out his plan to “evaporate CFS”; see advocate Craig Maupin’s blog, The CFS Report.
In February 2011, Dr. Gill presented at NIH (presentation video here at the 54:17 minute mark) he said: “Dr. Straus who was much younger than me and not with us anymore but my mentor in EBV and Chronic Fatigue finally wrote a paper near the end in 2004 about pharmacotherapy. All the things I just showed you. And I agree with what he said to this day that many therapies have been tried but so far only cognitive behavioral therapy and graded exercise appear to be meaningful, to produce meaningful benefit.”
Advocate Charlotte von Salis attended the presentation and blogged about it here. What follows is an excerpt from her blog: “Gill’s big on reassuring the patient, avoiding unnecessary tests, avoiding debate over whether it’s psychological, and above all, getting patients to remain active and exercise no matter what.”
Dr. Leorey Saligan is a family nurse practitioner/investigator who researches biobehavioral mechanisms of fatigue. He states that the reason that CFS patients report pain and fatigue is because they seek attention and are catastrophizers.
Below are just a few studies Saligan has been involved in:
Ways to Correct Problems with the Criteria and Investigators
Use a single criteria for the study - the ICC or the CCC.
Declare officially that NIH will not use the Reeves’ criteria and questionnaires (see references 11, 13 and 14) for any purpose in the study (see here for concerns about Reeves’ questionnaires). Replacement questionnaires (aka ‘instruments’ per clinical investigators) must be approved by ME experts and stakeholders.
Remove Walitt, Gill, and Saligan from the study and replace them with individuals with knowledge of ME as a biomedical disease who currently and historically do not ascribe to the psychosocial or psychosomatic causation of symptoms.
Problems With Executive Committee Advisors Who Are Not Experts In ME
Dr. Elizabeth Unger, CDC virologist, focused many of her studies and presentations on fatigue and the mind/body theory as she explained in this CFSAC video clip (posted by advocate Khaly Castle). As co-author of the Reeves' criteria, Dr. Unger explained in this video how her agency applies the criteria when asked by Eileen Holderman, former CFSAC Member, how CDC plans to reconcile the case definition issue. In the NIH study, Dr. Unger has been assigned to the executive committee and charged with reviewing diagnostic validity of the patient cohort. At the February 16th CDC Grand Rounds, Unger promoted graded exercise therapy (GET) and cognitive behavioral therapy (CBT), which is also promoted by the PACE Trial, for which ME experts have warned against as causing harm to patients.
Below are just a few studies Unger has been involved in:
Dr. W. Ian Lipkin is a world renowned virologist. In recent years, Dr. Lipkin has been investigating ME/CFS and collaborating with ME experts. Dr. Lipkin serves as an advisor on the study and will approve patient cohort selections. While Lipkin’s research shows great promise, he is not an expert in diagnosing and treating ME patients.
Ways to Correct the Problem with Advisors Without ME Expertise
NIH should seek advisors to the executive committee that have extensive experience investigating, diagnosing, and treating ME patients.
Advisors need to be approved by ME stakeholders.
Additional Problems with the Study’s Design
The cohort size of 40 ME patients is too small.
The study excludes patients who are the most severely affected such as the homebound and bedbound.
The use of recovered Lyme disease comparison control groups will obfuscate the results.
The summary of the study states they will conduct a bike exercise test twice, but does not specifically state the consecutive two-day CPET testing for post-exertional neuroimmune exhaustion.
The specific budget for this study has not been released and published.
Ways to Correct Problems with the Study’s Design
Increase the ME/CFS patient cohort size to increase probability of producing meaningful statistical results.
Include homebound and bedbound patients in the study. Historically, these patients have been under-researched and have the greatest potential to yield strong biomedical abnormalities.
Remove the asymptomatic recovered Lyme disease comparison control group from the study because they are prone to developing chronic Lyme disease (refer to here and here). In addition, the 2-tier testing used by the CDC for Lyme disease is not accurate. ME and chronic Lyme disease have overlapping symptoms and many ME patients are undiagnosed chronic Lyme disease patients due to a high level of false negative CDC test results. Therefore, this would obfuscate the comparison of these two disease groups.
Incorporate the consecutive two-day cardiopulmonary exercise testing (CPET) protocol into the study. The current bike exercise test, mentioned in the study summary, does not confirm whether post-exertional neuroimmune exhaustion occurs by documenting reduced VO2max on the second day.
Release and publish all budget information regarding funding for the study from its inception to conclusion.
Mistrust of Government Health Agencies and Problems with the Way NIH Communicates
The government health agencies have a history of malfeasance with this disease as documented by journalist and advocate Hillary Johnson in her book Osler’s Web. In 1985, the CDC went to Lake Tahoe, Nevada to investigate an ME outbreak and dismissed what they saw. They renamed the disease with a trivial moniker, chronic fatigue syndrome (CFS), and created a vague definition - both of which have caused serious harm to patients.
Additional abuses to the ME community include: CDC diversion of $12.9 million earmarked for ME/CFS research to other diseases; NIH underfunding biomedical research; Chronic Fatigue Syndrome Advisory Committee (CFSAC) FACA violations; HHS threats of eviction made to three CFSAC members; NIH/HHS FOIA violations and unreasonable conduct during the trial of FOIA violations (refer to Jeannette Burmeister’s blog on violations); and HHS dissemination of erroneous information about the disease to medical professionals, the media, and the public.
As illustrated, the patient community is justified in their mistrust of the government health agencies. Therefore, the burden is on the health agencies to rebuild the lost trust. NIH’s miscommunications are contributing to the mistrust.
Problems with the Way NIH is Communicating
Causing confusion by posting the intramural clinical study summary on clinicalstudies.info.nih.gov and clinicaltrials.gov websites then deleting the information (study numbers 16-N-0058 is the unofficial archive of original summary from clinicalstudies.info.nih.gov and NCT02669212 is the official archive of linked study on clinicaltrials.gov). Removing the initial study from the websites concealed the historical changes made to the study. Creating a webpage connected to the Trans-NIH ME/CFS Research Working Group describing the study. Creating another website for the NIH Intramural Study for ME/CFS.
Communicating information and conducting private meetings to only a select few advocates instead of the entire ME community.
Conveying conflicting information (by various agencies) about the study by various websites, presentations, and communications.
Sidestepping advocates’ questions and concerns (see examples below).
In his reply to advocate Joni Comstock’s question during the NIH Telebriefing, Dr. Walter Koroshetz stated: “ ...our intent is to reach out and get input from a wide variety of folks with expertise and with experience in this illness. And we have been doing that right from the beginning at NIH through the Trans-NIH Working Group, through the CFS Advisory Committee. We’ve had multiple meetings with experts in the field and with advocacy groups. And I must say it has been a challenge for us because there are, well we may not have reached out to everybody.”
Does “experts in the field” mean ME experts? NIH has not officially notified the community about specific ME researchers, clinicians or advocates who have been advising about the design of the study. There have been no assurances that ME experts and their input would be part of the study’s design and approval process.
Dr. Koroshetz further states: “And so, I think that the major teachers at the NIH really have to be the patients who have made the sacrifice to join the protocol, to come into the Clinical Center and to work with the doctors.”
By the time patient volunteers are involved, the design and protocol for phase 1 will have been set. Clearly, ME experts’ and stakeholders’ input and approval will not be be considered.
At The CDC Grand Rounds (You Tube video minute mark 53:23), Dr. Nath stated: “So, careful listening to patients is absolutely critical. So, with that in mind, you know I grew up in the early AIDS epidemic, and I saw interactive with Act Up, and other patient forums whereby they had a great impact on the way disease was handled, treated and moved the Federal government to make changes at every level. And so, we understand the importance of it, and there are efforts under way to put that advisory group together.”
Yet, at the NIH telebriefing, Dr. Nath stated: “So we looked into some of the legalities about patient advisory groups and it’s a little bit complicated in the federal government.” This implies that the assurance made by Dr. Nath at the CDC Grand Rounds regarding creation of a patient advisory group to provide input on the study may not occur because NIH does not want to deal with looking into an important but possibly complicated matter.
On one hand, NIH is telling the community they want patient and advocate input but on the other hand, NIH is implying that patients should just stick to telling them about their symptoms rather than advise them about the design of the study.
Ways to Correct the Problems with the Way NIH is Communicating
Reinstate the original protocol on http://clinicalstudies.info.nih.gov/ and clinicaltrials.gov, showing the changes that have been made. Also, remove the now inaccurate Trans-NIH Research ME/CFS Working Group “Eligibility Requirements for ME/CFS Clinical Study at the NIH” orphan webpage that still references functional movement disorder as a cohort. Release the history of the protocol to the public including protocol details and the Institutional Review Board (IRB) approval dates so that appropriate ME stakeholder input can be provided.
Communicate all information in real time to the entire community by using an NIH ME/CFS listserv.
Coordinate information across various agencies and sources so that all messaging is consistent.
Initiate and maintain a transparent and two-way communication process between NIH and the ME community (researchers, clinicians, advocates and patients) at every step of the study.
NIH Needs to Step Up!
For over 30 years, NIH and CDC have had a history of institutional bias, malfeasance and medical abuse toward the ME community. They have accomplished this by creating a trivial name and erroneous criteria, underfunding, and the promoting of harmful treatments such as GET and CBT. The Department of Health and Human Services (HHS) has ignored our ME experts’ biomedical evidence of abnormalities in the neuro-endocrine-immune systems of patients with ME - and instead used their own psychosocial and psychosomatic theories to describe a serious neuroimmune disease.
HHS needs to make concrete changes in order to affect real change in how ME is perceived and studied. Although NIH deems this study as only one piece of the puzzle, the Department has a record of turning that puzzle piece into a cornerstone of research dogma for decades to come.
Because of the opportunity for great discovery using the comprehensive resources that the NIH clinic has to offer, it is this very reason, we call for NIH to restart the study and include ME experts’ and stakeholders’ input throughout the entire process. The NIH study needs to use one criteria (the ICC or CCC), remove investigators and advisors without ME/CFS expertise and/or who possess a psychological bias (such as Drs. Walitt, Gill, Saligan, and Unger), eliminate comparison groups that will obscure study results, and communicate transparently to the entire ME community.
Now is the time for NIH to stop sidestepping the critical concerns ME stakeholders have about the study and step up to make the changes called for!
*Please note: MEadvocacy uses the term myalgic encephalomyelitis [ME] to describe the disease defined in the ICC or CCC. When we use the term ME/CFS or chronic fatigue syndrome [CFS], we are using the terminology due to the specific context in the blog. For information see www.MEadvocacy.org.
For Further Facts About ME, see MEadvocacy’s