Archive for January, 2015

The Biggest Chronic Fatigue Syndrome Treatment Trial Begins: Fluge/Mella On Rituximab

Doctor’s Fluge and Mella shocked the ME/CFS world with their 2009  case series and the 29-person 2011 study which found that about 2/3rds  of ME/CFS patients had a significant and positive response to the chemotherapy  and autoimmune drug Rituximab. With some patients achieving near miraculous recoveries, the results from Norway had the ME/CFS world buzzing.

rituximab-chronic-fatigue

The big question is – what percentage of ME/CFS patients will respond?

As encouraging as the results were, however, they were but a prelude to the big study ahead – the one that will definitively tell us how effective Rituximab is in this disorder.

As they begin the study, the doctors appear to be both cautious and optimistic. There’s no doubt now that Rituximab doesn’t significantly help some people with ME/CFS – the question is how many and how much – and that’s what this 152 person, multi-center study will tell us

Multi-dimensional in scope, it’s actually four studies in one – some of which are almost as exciting as the trial itself – that  could tell us much about ME/CFS. This very long study started up in the last quarter of last year – a bit later than expected. As  it did I asked the doctors some questions.

(Check  out the study on the ClinicalTrials.gov database).

How is the Rituximab (RituxME) study going? 

The RituxME study has just started recruiting patients. We plan to include 152 patients, in five centers in Norway. There will be 1:1 randomization between rituximab and placebo.

We will give the first two infusions two weeks apart (500 mg/m2, max 1000 mg, or placebo) followed by maintenance infusions 500 mg fixed dose (or placebo), at 3, 6, 9 and 12 months. The placebo solution with saline and some added albumin will look identical to the Rituximab solution. The study will be double-blinded and placebo-controlled.

The follow-up will be for 24 months, and the code for intervention will be revealed after the last included patient has been to 24 months visit and the database is locked.

measuring activity levels - me/cfs

Many measurements will be done – including activity levels.

Patients from 18-65 who have ME/CFS according to Canadian criteria (2003), age 18-65 ME/CFS for at least 2 years up to 15 years can be included.  People with severe, moderate/severe, moderate, mild/moderate and mild ME/CFS may be included.  If they have “mild” ME/CFS they need to have had the disease for at least 5 years. People with very severe ME/CFS (completely bedridden with need for help for all tasks) will not be included.

Self-reported symptom scores will be recorded every second week, and SF-36 questionnaires every third months. Activity levels will be assessed for seven consecutive days using the Sensewear armband at baseline, and repeated at the17-21 month follow-up.

Do you plan to publish the results of the open-phase trial? If not can you say anything about the results? (This was an open label (patients knew what they were taking) study with 29 patients using rituximab induction and maintenance treatment (six rituximab infusions over 15 months, with follow-up for three years, unpublished). This trial continued patients on Rituximab (a maintenance dose) for much longer, in a effort to reduce the relapses seen in some patients after they went off Rituximab.)

We have used the experience from our open-label phase-II study using rituximab maintenance. This study ended in February 2014, but due to all the work with the new study we have not had time to complete the manuscript. However, we are now completing the manuscript, and hope to submit soon.

We included 29 patients in the open-label phase-II study (KTS-2-2010). In this study there was no placebo group, and that will of course be the main criticism of the study. The reason for doing an open-label study was to gain experience on dose-response relationships in order to better design the randomized phase-III study. We also wanted to give patients who had taken the placebo in our first randomized study (Plos One 2011, KTS-1-2008) an opportunity to take part in a study without being randomized again (that was in agreement with the ethical committee approving the KTS-1-2008 study).

One patient had an allergic reaction at the first infusion and did not get further intervention, leaving 28 patients to receive rituximab maintenance treatment. The patients received two infusion with rituximab two weeks apart,  followed by maintenance rituximab infusions after 3, 6, 10 and 15 months (7 patients received further infusions according to an approved amendment in the study).

We will not give details on the results here, even though the study has been presented at some meetings the last year. For now we can state the response rate was quite similar to the first KTS-1-2008 study, and that the response durations seem to be much prolonged (as compared to the Plos One study) when giving rituximab maintenance treatment.

Rituximab-chronic-fatigue

Fluge and Mella’s data indicated that maintenance doses of Rituximab worked: i.e. they largely kept patients from relapsing

To us, the most important issue now is to do a proper phase-III study which will determine if the results of the first trial can be trusted. It is important to understand that our first phase-II study (Plos One, 2011) – the first to evaluate the treatment principle of B-cell depletion in ME/CFS – had several limitations.

We do not know how much selection bias was present in our first two studies. If the putative immunological disease that we have seen is commonly found in the broad groups of ME/CFS patients that fulfill the Canadian criteria, we have a chance to get a significant result in favor of rituximab in the ongoing study.

However, if our selection bias in the first studies is large (i.e. if we selected out patients that are not representative of ME/CFS patients as a whole) the new study might very well turn out negative (i.e. no difference to placebo). Should that happen we would then focus our efforts on figuring out how to select the subgroup that has an   immunological, rituximab-responsive disease.

The Substudies

Blood vessel, exercise and gastrointestinal substudies occurring alongside the major study could tell us much about ME/CFS as well. Some of the substudies are, to my mind, almost as interesting as the Rituximab study itself. I asked Dr. Fluge about them. 

For the RituxME study, we will perform three substudies. (We originally planned to use these in the main study, with some parameters as secondary endpoints, but because all centers could not perform the analyses they were designed as substudies.)

All three substudies will be performed at baseline and repeated at the 17-21 months follow-up, which is the time interval our previous experience suggests that the therapeutic effect of rituximab maintenance to be most evident.

Endothelial Functioning Substudy

Our substudy of endothelial function (Bergen Notodden) in 72 patients will use flow-mediated dilation to test large blood vessel endothelial functioning.  We will also test microvascular endothelial function in Bergin using skin laser-doppler measurements.

blood vessels chronic fatigue

Is a problem in the blood vessels triggering the sympathetic nervous system activation found in ME/CFS?

We believe that endothelial function is important in ME/CFS. Even though many symptoms can be ascribed to the central nervous system we are not convinced that ME/CFS is primarily a central nervous system disorder. We believe the sympathetic nervous activation seen in ME/CFS may be (partly) secondary to an underlying (peripheral) pathology.

It is important to get an understanding of which symptoms that are caused by the primary pathology, and those which may be ascribed to secondary (compensatory) mechanisms.  We are working to elucidate whether endothelial dysfunction, and subsequent inadequate fine-tuned autoregulation of blood flow to meet the demands of tissues, may be an important feature of ME/CFS.

A study from Dundee in 2011 showed endothelial dysfunction to be present in ME/CFS. Our pilot studies in a group of ME/CFS patients suggest it is as well.

In the substudy to RituxME, we ask if we can reproduce the endothelial dysfunction in a larger cohort of ME/CFS patients? Is there a relation between endothelial dysfunction and disease severity? Is there a relation between endothelial function and a later clinical response (in the rituximab group)? In patients that improve after B-cell depletion therapy (Rituximab) is there a relation between improvement in self-reported symptoms or in physical activity levels, and changes in endothelial function?

We have written a manuscript on our thoughts and hypotheses including the relation between immune response, endothelial function, and the possible effector system for symptom maintenance in ME/CFS. However, we still believe that we need more data to underpin out thoughts and have therefore not submitted the paper yet.

[Dysfunction of the endothelial cells lining the blood vessels in the circulatory system has been a subject of interest in ME/CFS since MERUK’s pioneering efforts in the early 2,000’s. These cells  – present everywhere from largest arteries to the small capillaries – control how dilated or narrowed the blood vessels are, affect inflammation, control blood clotting and more.  Each of these factors have been implicated in ME/CFS at one time or the other. In 2012 Newton et al.  reported both small and large blood vessel dysfunction was present in ME/CFS.

The finding last year that  autoantibodies to the adrenergic receptors found on endothelial cells are present in postural orthostatic tachycardia syndrome (POTS) suggested an autoimmune process was knocking out one group of POTS patients. Now Fluge/Mella appear to be proposing that a similar autoimmune process is messing up the blood vessels and producing the sympathetic nervous system activation in ME/CFS. If that’s so Rituximab’s efficacy could lie in its ability to restore proper blood flows (and presumably blood volume) to ME/CFS patients allowing them to exercise, think, digest, etc. as healthy people do.  This is a hypothesis that is pregnant with possibilities.

Fibromyalgia patients should note that Rice has found evidence of small blood vessel dysfunction in the hands that may also be impeding normal blood flows throughout the body. – Cort. ]

 Exercise Substudy

The cardiopulmonary exercise tests for two following days will be performed at baseline and repeated in the 17-21 months follow-up. We will do this substudy in Bergen, Notodden and Oslo, but only for patients with mild and moderate disease (not severe), The total number may be 50, perhaps more.

exercise chronic fatigue syndrome

The ultimate test of Rituximab’s effectiveness – an aerobic exercise test.

We want to see (in a double-blind fashion) if the performance (VO2max, VO2 at anaerobic threshold, workload at max and at anaerobic threshold) of patients who respond to Rituximab will improve on day two of the exercise test.

It may be a disadvantage that we exclude patients with a high symptom burden from this substudy, but we did not want to put patients with moderate/severe or severe ME/CFS through such physical exertion because they may worsen for many following weeks. They will also start the intervention (Rituximab or placebo) three weeks after these tests  – maybe too soon for some moderate/severe or severely ill patients to fully recover.

Gastrointestinal Functioning Substudy

The substudy on gastrointestinal function will only performed in Bergen, and only for patients with GI symptoms resembling functional dyspepsia or irritable bowel disease. Approximately 15-20 patients will be included.

Gastroenterologists in Bergen will evaluate the patients using several self-reported forms, and with a soup meal followed by ultrasound assessment, and also with endoscopy and biopsies from those willing to participate in this (in fact, most of those we have evaluated are willing to do the endoscopy!). The GI studies will be performed at baseline and repeated after 17-21 months.

Genetics Study

Dr’s Fluge and Mella will  also be looking at the genetics of ME/CFS patients and their families. Dr. Fluge wrote

genetics-chronic-fatigue

The list goes on…Fluge and Mella are also looking at genetics

To further elucidate possible clues, we are also working on exom-sequencing of families with many affected individuals among first- and second-degree relatives, sequencing all coding parts of the genome (with flanking introns) both from affected and healthy family members. We test candidate genes with targeted sequencing in all patients included in our studies. We hope to be able to link the genetic and clinical data, to underpin the hypotheses.

An Autoimmune Disorder?

I asked Dr. Fluge why they thought the patients responding to Rituximab may have an autoimmune  disorder?

Why we think this is a variant of an autoimmune disease? First, we have not shown that ME/CFS is an autoimmune disease. However, we believe that in a subgroup of patients an autoimmune pathogenesis involving B-lymphocytes and possible immunoglobulins (autoantibodies) makes sense.

The arguments are as follows:

  • The observed pattern of responses and relapses after rituximab treatment, with a lag time of several/many months from initial and rapid B-cell depletion until start of clinical responses. Such patterns are also seen in established autoimmune diseases after rituximab treatment, such as Wegener’s granulomatosis and rheumatoid arthritis.
  • A high proportion of women with ME/CFS
  • Our studies suggest a high occurrence of autoimmune diseases exists among relatives of ME/CFS patients (could also be a marker for a selected population in our studies?)
  • A moderate, but highly significant risk of B-cell lymphomas in elderly ME/CFS patients, shown in a large case-control study from National Cancer Institute in 2012. To me, this is an important study, showing that patients may have a chronically activated B-cell system.
  • Emerging data from a few other poorly understood diseases (POTS, Chronic Regional Pain Syndrome, CRPS) which have some common characteristics and possibly to some extent may overlap with ME/CFS, in which research groups have detected (functional) autoantibodies.

Long Lag Time Also Suggests Autoimmunity

Epstein-barr chronic fatigue

The different responses Fluge/Mella’s ME/CFS patients and their chronically activated EBV patients have had to Rituximab suggest to them autommunity, not EBV reactivation, is ocurring.

The long lag time from rapid initial B-cell depletion to start of the clinical response (2-8 months) is why we do not think elimination of EBV or CMV is the principle mechanism for symptom relief in our patients. In my work as a lymphoma oncologist, I have treated a few patients with chronic EBV infection, with moderate lymphadenopathy, night sweats and general symptoms for several years, and with no clear clinical benefit from valganciclovir.

In one patient, the B-cells in bone marrow and in lymph nodes were packed with EBV and she had a high EBV titer in her peripheral blood. When given rituximab, her symptoms waned in a few days after start of treatment – very different from what we see when treating ME/CFS patients.

Two Cautionary Notes

Dr. Fluge wanted to make two cautionary notes: 

caution rituximab chronic fatigue

Caution! Rituximab use in severely ill patients is not recommended…

Very severely ill ME/CFS patients – We are also conducting a study (KTS-3-2010), which includes very severely ME/CFS patients. Only four very severely ill ME/CFS patients have been at our hospital, and it is very difficult to give them the care they need in a very busy oncology ward. For these for patients, although rituximab has influenced their disease in a slightly positive manner for two, none of the four could be characterized as responders. We do not encourage treatment of patients with very severe ME/CFS with rituximab outside clinical trials!

In fact, until further scientific data and evidence are available, all patients receiving rituximab for ME/CFS should be treated within clinical trials.

Etanercept - We started a clinical open-label phase-II study on weekly subcutaneous etanercept (a TNF-alpha inhibitor). Only four patients were included, and we decided to stop the trial because two patients had a clear worsening of ME/CFS symptoms, while two were unchanged (no response). Ideally, we should have included additional patients to gain experience for a more solid conclusion; we however decided to stop the trial.

New Open Phase-II Trial

After observing a few pilot patients for one year, we have decided to begin another open-label phase-II study in Spring 2015 on another immunomodulatory drug, in three sets of ME/CFS patients:  ME/CFS patients who have not treated before with rituximab, in nonresponders to rituximab treatment, and in patients with a clear response to rituximab but with evidence of gradual relapse the last year. This study has been approved by the Ethical Committee, and will occur at a single center study in Bergen (Haukeland University Hospital)

Conclusion

In conclusion, we hope our efforts will help to increase our knowledge of ME/CFS, and that the results of the new randomized study will provide some important answers to aid further research, either by us or others in the research community. We need a better understanding of the disease with regards the genetic predisposition, the immune disturbances and the endothelial dysfunction present and the effector systems for symptom maintenance in order to develop rational treatments for this devastating and misunderstood disease.

 

 

 

 

 

 

 

 

 

 

 

 

P2P Report Urgently Calls for Major Increases ME/CFS Research: Tightening Needed

January 19, 2015

“We hope our work has dignified ME/CFS and those affected, while providing expert guidance to the NIH and the broader research community.” – P2P Executive Draft Summary

pathways-to-prevention

ME/CFS is the third disorder to go through the P2P program

The Pathways to Prevention Program (P2P) is an NIH program begun in 2012 that is tasked with identifying research gaps, methodological weaknesses and suggesting research needs for disorders that cause major health problems but are not being addressed well by the medical field.  The limited published data and few randomized controlled trials in these disorders of “broad public health importance” have made it difficult to produce systematic reviews.

That chronic fatigue syndrome is only the third disorder or condition — after polycystic ovary syndrome and opioids and chronic pain — to go through the P2P process, suggests the NIH may be increasing its commitment to this disorder.

The Panel was tasked with (1) identifying research gaps, (2) determining methodological limitations, and (3) providing future research recommendations regarding diagnosis and treatment.

Panelists “Get” Community Needs

In the first part of the P2P Draft Report it was gratifying indeed to see a panel of outsiders – none of whom had any connection to chronic fatigue syndrome (ME/CFS) – “get” the major issues facing the chronic fatigue syndrome community.  In retrospect perhaps it’s not so surprising; people who take the time to get to know the ME/CFS community and the problems it faces have become allies in the past.

big-leap

Major gaps in every area were identified…Will the panel recommendations help to surmount them?

The first part of the report  identified numerous gaps that are keeping the field from progressing. In the second part they provide a long list of recommendations that would, if acted upon, result in significant and long-sought progress in this field. The panelists appear to have thrown virtually everything they can think of at this disorder which has so many needs.

The lack of specific funding recommendations or time or numerical targets, however, left me wondering if panel understands the kind of cultural shift that has to occur at the NIH before ME/CFS gets its due. The panel is up against a culture of dismissal that has even been willing to ignore its own studies showing that high prevalence rates, disability rates, high economic losses, and enormous unmet needs are present.

The NIH, we know, will very likely do everything it can to ignore, distort, wave off, and pretend to comply with the P2P report’s recommendations.  Jennie Spotila and Mary Dimmock have pointed out the federal government can be very good at taking the least possible action to fulfill minor recommendations while ignoring or not acting on major recommendations. Does the panel, for instance, recognize

  • head-in-sand

    The P2P is up against an embedded culture of neglect and dismissal at the NIH

    that this million-person disorder has been in the bottom five percent of NIH funding for decades?

  • that adjusted for inflation the NIH is spending about what it did on ME/CFS twenty years ago -when it was considered a small, niche disorder?
  • that disorders of ME/CFS’s prevalence, effects, and economic losses typically receive twenty times as much funding?
  • that most major cities in the U.S. do not have one expert ME/CFS practitioner?
  • that the NIH’s response to that dearth of ME/CFS experts has been to turn down requests for Centers of Excellence year after year? That over a decade of requests has not produced one COE?
  • that similar disorders such as fibromyalgia, which also affect large numbers of people (often women) and produce severe economic losses, but do not usually kill, are in a similar situation?

The panel recognizes help is needed in every aspect of this field and the P2P report is going to help – there’s no doubt about that – the only question at this point is how much. With that in mind, I propose ways to tighten up some recommendations and add some others. I believe the Panel must be as specific as possible and not allow wiggle room.

First the gap is presented, then the recommendation, and then ways to tighten it up. I look forward to hearing suggestions from others.

January 16th is the last day to submit comments using this email address:  prevention@mail.nih.gov. They ask that each comment reference the line number of the report it’s referring to. 

The P2P Panel’s Recommendations to Fill Gaps in ME/CFS Research and Treatment

“Innovative biomedical research is urgently needed to identify risk and therapeutic targets, and for translation efforts.“ – P2P Draft Report

GAP: A Definition Needed to Provide the Foundation for Research and Clinical Trials

The panel endorsed a large-scale effort to finally find a suitable definition for ME/CFS that included creating a team of stakeholders, creating a research network, and examining commonalities with other disorders.

team-building

A team of stakeholders should agree on a definition

Create Team of Stakeholders – The panel recommends creating a team of stakeholders (patients, clinicians, researchers, and federal officials) that will come to consensus on a definition now, even if it’s an imperfect one.

That’s almost been done; the Canadian Consensus and International Consensus Criteria involved patients, clinicians, and researchers, but not federal officials.  The advocacy letter requesting that the NIH adopt the Canadian Consensus Criteria (CCC) indicated also that a large number of stakeholders agree that the CCC should be adopted, but also did not include federal officials.

A National and International Research Network should be developed to clarify the definition and “advance the field”.  This is an important part because no suitable research definitions are present at the moment. The CCC and ICC are fine clinical definitions, but studies suggest they may result in selection of a high percentage of ME/CFS patients who also have psychiatric disorders and allow a significant percentage (15-20%) of healthy people to be identified as having ME/CFS.  A better research definition can be developed.

leaking-pipe

Tightening the recommendations is recommended.

Tightening

  • NIH shall develop a National Research Network consisting of 3-5 centers in the US each with a dedicated research budget of $5 – 10 million and make efforts to enroll other countries in producing similar centers. A funded grant opportunity (Request For Applications (RFA)) should be issued within one year to produce the outcome measures and studies needed create a validated research definition. (See research section for more.)

Identify Commonalities and Co-morbidities with Other Disorders – Produce a Conference to Highlight Them -   the panel recommended that Gulf War Syndrome, Lyme disease, fibromyalgia, multiple sclerosis, and Parkinson’s disease be studied alongside ME/CFS to discover commonalities and differences. A conference to enable discussion and interaction between researchers studying these disorders should occur.

Tightening

  • An NIH sponsored conference to examine commonalities and differences among ME/CFS, Gulf War Syndrome, Lyme disease, fibromyalgia, multiple sclerosis, and Parkinson’s disease and others should take place within one year.
  • The conference should lay the foundation for a $5 million RFA to further explore commonalities and differences in these disorders.

GAP – New Knowledge is Needed

Bench to Bedside ME/CFS Research is Recommended.

Bench to bedside or translational research is what Centers of Excellence do: they research (bench) and treat patients (bedside) in the same facility, yet the panelists don’t specifically recommend them — although they do recommend something that appears to be similar (See Collaborative Centers recommendation below.)

Tightening

  • Five Centers of Excellence should be established within two years, and five more within five years. (See Network  of Collaborative Centers below.)

GAP: Many Research Needs Are Present

“Determining the most important physiologic measures and pathophysiology, as well as genome-wide association studies (GWAS) and phenotyping, is essential for stratifying patients.”

test-tubes-blood

Many research needs were identified

The P2P panel recommends that a broad and deep effort employing the latest technology be mounted to understand the pathophysiological mechanisms at play in ME/CFS. Specifically they recommended priority be given to efforts to:

  • Develop biomarkers using genomic, epigenomic, proteomic, and metabolomic strategies.
  • Identify subsets using physiologic markers and genome-wide association studies (GWAS).
  • Use fMRI and other imaging studies to understand the neurological problems in ME/CFS.
  • Use cutting–edge technologies such as high throughput sequencing and neuroimaging to investigate the effects the gut microbiome has on ME/CFS.
  • Identify who is at high risk of getting ME/CFS, chart the geographical distribution of the disorder, and illuminate health care disparities (who has access to good medical care and who does not).
  • Develop algorithms to determine who is at high risk of coming down with ME/CFS after an infection.
  • Put the data from large “-omics” (genomics, proteomics, metabolomics, etc.) studies in publicly accessible databases that enable researchers to use data mining techniques to understand the  molecular mechanisms present, to do pathways analyses, and to aid drug companies in drug discovery/drug repurposing.
  • Identify immunological mechanisms and pathways (cytokines, inflammation, NK cell dysfunction) that contribute to the progression of the disease.
  • Use twin studies to identify differences in gene expression.
  • Investigate the effects (if any) of homeopathy, non-pharmacologic, complementary, and alternative medicine treatments. Studies addressing biopsychosocial parameters (including the mind-body connection), function, and QOL should be encouraged.

A National Biobank – A national registry/repository should be created to house the results of these studies and to help researchers better understand the pathogenesis, prognosis, and biomarkers present  in ME/CFS.

upwards

A key recommendation: spending on ME/CFS research be brought in line with that found in other disorders if similar size, prevalence and economic costs

Issue : The panel’s recommendation that a broad range of pathophysiological targets be explored is very helpful. Their unwillingness, however, to recommend specific federal spending targets, or specific grant programs (RFAs) could allow the federal government to fund one or a couple of studies from each section and say they met the recommendations.

The NIH is currently funding, for instance, at least one neuroimaging study, a gene expression after exercise study, a natural killer cell study and a microbiome study. Funding one or two studies in an area every four to five years means more of the glacial pace of progress that has characterized this field for decades. This is not the rate of progress that patients, the panel earlier noted, want and deserve, and it’s not the outcome that the P2P panel, judging from its otherwise very helpful report, wants to see.

Tightening

  • The NIH bring pathophysiological research funding for ME/CFS into line with that provided for disorders of similar size, economic losses, and disability rates (excluding comorbid disorders such as fibromyalgia, interstitial cystitis, etc. which receive low funding) within five years.
  • The NIH should produce a series of $5 million RFAs over the next three years to address critical questions regarding the role the immune, autonomic, and central nervous systems and metabolism play in ME/CFS.

GAP: Inadequate Methods and Measures to Assess Treatments and Identify Subgroups

tools

A Working Group should identify the right tools to assess ME/CFS

Throughout the report the panel referred to inadequate outcome and other measures. The NIH has been saying this for years, but without doing anything about it.  Now they get their chance.

Establish Methodological Working Group – to oversee the development of these measures, plus:

  • Online tracking tools should be utilized.
  • Immobile patients should be included.
  • A community-based research approach should be used to increase patient involvement in determining priorities for research and patient care.
  • Assess psychiatric comorbidities to assist with measurement of quality of life.
  • Long-term longitudinal studies already underway should include ME/CFS.

GAP: Provider Education Lacking

Few physicians understand how to treat or even to recognize chronic fatigue syndrome.

  • Use  accreditation and licensing programs to produce ME/CFS curriculum.
  • Use Health Resources and Services Administration (HRSA) to facilitate training.

Tightening

  • Create accredition program to license ME/CFS practitioners.

 GAP: Finding New Funding

The panel’s statement that a “relatively small number of researchers” are present in the field vastly overstates the number of researchers studying ME/CFS relative to other disorders and suggests the panel may not have quite gotten to the depth of the NIH’s neglect.

In the Finding New Funding Resources section a number of good, but at times somewhat vague, recommendations are given to address funding needs. The recommendation to create collaborative research centers is a highlight.

Create a Network of Collaborative Centers

research-network

A collaborative research network should be created to move the field forward.

The centers should determine diagnostic and prognostic biomarkers, do epidemiology (e.g., health care utilization), determine functional status and disability, create patient-centered QOL outcomes, and determine the cost-effectiveness of treatments and the role of comorbidities in clinical and real-life settings.

This promising recommendation with its research and treatment components sounds very similar to COE’s. Unless the panel is more explicit, though, the NIH could create two small, overburdened centers and say “job done”.

Tightening

  • Recommending that the NIH fund five COEs, each with a $5 million budget (?) over the next two years, and five more over the subsequent five years would go a long way toward enhancing research and improving access to medical care in  major cities.

Others

  • NIH institutions need to partner together to advance the research and develop new scientists for ME/CFS.
  • More investigator-initiated studies (grant applications) are needed. (How many more? And how? By producing RFAs?)
  • Career development pathways for ME/CFS researchers should be developed.
  • Small grants should target younger investigators to get them into the ME/CFS field.

The ME/CFS field desperately needs new researchers and younger researchers and career development pathways. That would be superb… but what it really needs – and what would solve most of these problems – is dedicated funding for research and, so far as I can tell, that means grant opportunities that come loaded with money; i.e. RFAs. While the spirit of the report suggests funded grant opportunities or RFA’s would be necessary to carry out the panel’s recommendations, the panel has not specifically recommended them.

Tightening

  • Patients, ME/CFS experts, and federal officials will work together to set a target for the number of investigator-initiated studies needed to bring research funding into line with the disorder’s effects and come up with ways to meet that target, including RFAs.
  • The NIH will produce a series of $5 million dollar RFAs over the next three years to address critical questions regarding the role the immune, autonomic, and central nervous systems and metabolism play in ME/CFS.
  • Smaller grants targeting young investigators should be produced every year for the next five years. At the end of five years the effectiveness of the small grant project should be assessed.

Adding Working Group Members

failure

Adding more working group members to a group that does not work will not help

Issue – This statement, “Opportunities exist within HHS to engage new ME/CFS working group members, to create efficiency, and to co-fund research that will promote diversity in the pipeline, eliminate disparities, and enhance the quality of the science,” reflects the panel’s understandable ignorance of the structural problems facing ME/CFS at the NIH.

The Working Group is at the top of the list of factors that have stifled – not advanced – opportunities for ME/CFS.  If the last fifteen years has shown anything, it has shown that relying on the Institutes to do anything meaningful under the aegis of the Working Group is a pipe dream.

With the buck not stopping at any of the institutes in the Working group, it’s easy to see why all have essentially washed their hands of it. Adding more members (NIMHD or NCI) to the already long list of Working Group members would, unfortunately, change nothing.

Tightening

  • Recommend that a commission of patient advocates, ME/CFS experts, and federal officials assess the effectiveness of the Working Group in supporting ME/CFS research,  identify structural factors that are impeding funding for ME/CFS, and provide recommendations for change.

GAP: More Clinical Trials Needed

  • Create a website for patient and clinician educational materials and clinical trials.
  • Utilize the NIH Clinical Center for clinical trials.
  • Explore opportunities to fast-track new therapies.

Multimodal treatment – The panel should take note of the enormous numerical disparity between behaviorally-oriented treatment trials and all other kinds of trials found in ME/CFS. The fact that CBT and GET have been the focus of some thirty clinical trials while no other treatment modality has, to my knowledge, received more than one, indicates the powerful  hold that behavioral studies, many of them UK and European government funded,  have had in the clinical trial arena.

While the panel stated that neither CBT nor GET should be considered a primary treatment, it might reflect that, given the history of bias in this disorder, that recommending multimodal clinical trials could be interpreted as recommending a biopsychosocial approach to treatment – an approach that has failed, after many efforts, to get at the cause of ME/CFS.  With so many other compelling research needs present, putting more money into that approach would be counterproductive.

Tightening

  • Multimodal – The panel should make explicit its recommendation regarding multimodal trials to ensure such trials involve drugs and other such treatments that affect pathophysiology.
  • FDA –  New pathways for drug development need to be developed that take into account the barriers found in large, poorly studied heterogeneous disorders that get little interest from drug companies such as ME/CFS.. A panel of patient advocates, ME/CFS physicians and experts, federal officials, and drug company officials should identify those barriers and provide recommendations to surmount them.

Patient Participation Emphasized

“Patients must be at the center of the research efforts, and their engagement is critical” – P2P Draft Report

The panelist made explicit one feature that applies to most of it’s the recommendations: patient involvement is necessary.

Conclusions

funding

Following the P2P reports recommendations would require the federal government to spend money – much more money on ME/CFS…Will they?

In their conclusions, the panel added more recommendations, among them that the Oxford definition be retired. In the interim, they recommended multimodal therapies be employed until a cause and primary therapies are developed. They recommend that federal departments, advocacy groups, and industry work together in public-private partnerships to help advance research for ME/CFS. Federal agencies (e.g., AHRQ, the U.S. Department of Veterans Affairs [VA]) and professional societies should work together to create quality metrics and a standard of care.

Were the federal government to follow the spirit and letter of the P2P draft summary recommendations they would need to — for the first time –spend some real money on ME/CFS. That would probably require re-organizing the way the program is currently maintained and funded. ME/CFS has little chance of advancing significantly under its current structure, and a re-evaluation of the program’s funding mechanisms should be a natural outcome of a report that has exposed so many needs after almost thirty years of research.

The P2P recommendations are not perfect. I believe they need to be significantly tightened up, and numerical targets, in particular, be attached to them. It’s puzzling in particular to me, given the lack of research funding, that the panel did not explicitly call for RFAs.

The panel is essentially recommending, however, that the federal government finally get serious enough about the ME/CFS field to provide it the benefits that other major disorders enjoy: sufficient research funding, collaborative networks, Centers of Excellence, RFAs, validated outcome measures, and a place in the medical curriculum. That would include educating doctors,and enrolling young new researchers in ME/CFS career paths. It’s a potential game-changer.

Now it’s up to us to support the federal government in carrying out the recommendations their own panel has produced.