“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
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.
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
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: firstname.lastname@example.org. 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.
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.
- 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.
- 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.)
- 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 Present
“Determining the most important physiologic measures and pathophysiology, as well as genome-wide association studies (GWAS) and phenotyping, is essential for stratifying patients.”
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.
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.
- 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
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.
- 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
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”.
- 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.
- 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.
- 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
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.
- 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.
- 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.
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.
January 16th is the last day to submit comments using this email address: email@example.com. They ask that each comment reference the line number of the report it’s referring to.
CFSAC will have a special meeting via conference call to discuss the P2P report on Jan 13, 13, 2015, from 1:00-3:00 pm (ET). Comments on the report need to be submitted by Jan 7th to firstname.lastname@example.org.
Keep the Information Flowing!
Tell us how your coronavirus vaccination went and find out how other people with ME/CFS and/or FM fared with their coronavirus vaccination in Health Rising’s Coronavirus Vaccine Side Effects Poll.